{"gene":"AKAP5","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1996,"finding":"AKAP79 functions as a scaffold protein that simultaneously binds PKA, calcineurin (PP2B), and PKC at distinct sites, coordinating three signaling enzymes at the postsynaptic membrane.","method":"Deletion analysis, binding studies, co-immunoprecipitation, immunofluorescence in neurons","journal":"Science","confidence":"High","confidence_rationale":"Tier 1–2 — foundational study with multiple orthogonal methods, replicated extensively by subsequent labs","pmids":["8599116"],"is_preprint":false},{"year":1993,"finding":"AKAP75 (bovine ortholog of AKAP5) contains two noncontiguous N-terminal domains (residues 27–48 and 77–91) that mediate intracellular membrane targeting, and a separate C-terminal RII-binding (tethering) domain mapped to residues 392–413 via scanning mutagenesis, where hydrophobic residues are essential for high-affinity PKA-RII binding.","method":"Deletion mutagenesis, scanning mutagenesis, subcellular fractionation, RII overlay assay in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis with defined domain mapping, foundational study","pmids":["8509414"],"is_preprint":false},{"year":1997,"finding":"Ca²⁺/calmodulin binds AKAP79 at the same N-terminal region (residues 31–52) that binds PKC, competing with PKC for binding and releasing the inhibited kinase from the anchoring protein; calmodulin binding also reverses AKAP79-mediated inhibition of PKCβII.","method":"Calmodulin binding assays, co-immunoprecipitation from postsynaptic density preparations, immunofluorescence in hippocampal neurons, PKC activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal biochemical methods, functional readout","pmids":["9202019"],"is_preprint":false},{"year":1998,"finding":"AKAP79 membrane targeting is mediated by three basic/hydrophobic N-terminal regions (A: residues 31–52; B: 76–101; C: 116–145) that bind acidic phospholipids including PIP2; this binding is disrupted by phosphorylation and Ca²⁺/calmodulin, providing a regulatory mechanism for membrane release.","method":"GFP-tagging and in situ fluorescence targeting assays in HEK293 cells and cortical neurons, lipid vesicle binding assays, subcellular fractionation after PKA/PKC activation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including mutagenesis, lipid binding, and cell fractionation","pmids":["9545238"],"is_preprint":false},{"year":1998,"finding":"AKAP79 binds calcineurin A (CnA) at residues 30–98 and 311–336 of CnA, with the AKAP79 binding site on residues 108–280; this interaction does not require the calcineurin B subunit, occurs at a site distinct from immunophilin binding, and AKAP79 inhibits NFAT dephosphorylation and activation in intact cells.","method":"Co-immunoprecipitation, deletion mapping, NFAT reporter assay in transfected cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal mapping with functional validation via NFAT reporter","pmids":["9765270"],"is_preprint":false},{"year":1999,"finding":"AKAP79 binds PKC at the catalytic core through the N-terminal region (residues 31–52) in a lipid- and activation-independent manner, inhibiting PKC activity by displacing the pseudosubstrate domain; residues R39 and R40 in the AKAP79(31–52) peptide are essential for PKC inhibition. AKAP79 associates with conventional, novel, and atypical PKC isoforms.","method":"In vitro binding and kinase activity assays, limited proteolysis, site-directed mutagenesis, co-immunoprecipitation, immunofluorescence in hippocampal neurons","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro mechanistic assays plus mutagenesis with multiple PKC isoforms","pmids":["10510312"],"is_preprint":false},{"year":2001,"finding":"AKAP79 regulates GRK2-mediated phosphorylation of the β2-adrenergic receptor by facilitating PKA phosphorylation of GRK2 at Ser685, which increases Gβγ binding to GRK2 and promotes its membrane translocation and receptor phosphorylation; disruption of this pathway reduces receptor internalization.","method":"Overexpression/dominant-negative approaches, mutagenesis (GRK2 S685A), co-immunoprecipitation, receptor internalization assays in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — site-directed mutagenesis with defined phosphorylation site and functional cellular readout","pmids":["11278469"],"is_preprint":false},{"year":2001,"finding":"AKAP79 directly associates with the inwardly rectifying potassium channel Kir2.1 via both the intracellular N- and C-terminal domains of the channel, and this association enhances Kir2.1 responsiveness to elevated intracellular cAMP.","method":"Co-immunoprecipitation, GST pulldown, electrophysiology in intact cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP and GST pulldown with functional electrophysiology, single study","pmids":["11287423"],"is_preprint":false},{"year":2002,"finding":"The PP2B/calcineurin-anchoring site on AKAP79 maps to residues 315–360, which are necessary and sufficient for PP2B anchoring in cells, directly bind the PP2B A subunit, and inhibit phosphatase activity; peptides spanning this region antagonize PP2B anchoring and attenuate PP2B-dependent down-regulation of GluR1 currents.","method":"Deletion/truncation mutagenesis, cell targeting assays, in vitro phosphatase activity assays, peptide competition, electrophysiology in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro phosphatase assay plus mutagenesis plus electrophysiological functional readout","pmids":["12354762"],"is_preprint":false},{"year":2002,"finding":"AKAP79 directly regulates cell surface expression (trafficking) of L-type CaV1.2 calcium channels independently of PKA, through interaction involving a short polyproline sequence in the channel II–III cytoplasmic loop.","method":"Extracellular epitope tagging, immunoassays, whole-cell and single-channel electrophysiology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — direct channel expression assay with electrophysiology, mutagenesis of binding sequence","pmids":["12114507"],"is_preprint":false},{"year":2002,"finding":"AKAP79 is linked to GluR1 AMPA receptors via SAP97, promoting basal PKA-dependent phosphorylation of GluR1 Ser845, and the AKAP79–PP2B complex confers Ca²⁺-dependent downregulation of GluR1 currents mimicking LTD; this requires the PDZ interaction between GluR1 and SAP97.","method":"Co-immunoprecipitation, electrophysiology in HEK293 cells and hippocampal neurons, mutagenesis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, defined molecular mechanism with functional readout","pmids":["11943807"],"is_preprint":false},{"year":2002,"finding":"AKAP79 assembles a ternary kinase-scaffold-phosphatase complex at the plasma membrane, where PKA-RII and calcineurin bind simultaneously to AKAP79 within ~50 Å of each other, as demonstrated by FRET in living cells; AKAP79 also regulates membrane localization of SAP97.","method":"FRET microscopy (donor-dequenching and sensitized emission), immunofluorescence in living cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — direct FRET evidence of ternary complex in living cells, multiple FRET configurations","pmids":["12507994"],"is_preprint":false},{"year":2003,"finding":"AKAP79 interacts with IQGAP1 through the carboxyl-terminal domain of IQGAP1, forming a complex that links PKA to the IQGAP1 scaffold in β-cells.","method":"cAMP affinity chromatography co-purification, co-immunoprecipitation, direct interaction assay","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — single pulldown/co-IP study without functional follow-up","pmids":["12938160"],"is_preprint":false},{"year":2005,"finding":"AKAP79 (constitutively associated with β2-AR) provides the PKA that mediates β2-AR phosphorylation enabling switching of β2-AR signaling from Gs to Gi/ERK activation; PDE4D5 recruited by β-arrestin desensitizes this PKA-mediated switch.","method":"siRNA knockdown of specific AKAPs and PDE4 isoforms, co-immunoprecipitation, PKA activity assays, ERK phosphorylation assays in HEK293B2 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — isoform-selective siRNA with multiple functional readouts, identifies specific AKAP and PDE isoforms","pmids":["16030021"],"is_preprint":false},{"year":2006,"finding":"AKAP79 forms a ternary complex with β1-adrenergic receptor and PKA at the receptor C-terminus, and AKAP79-anchored PKA phosphorylates β1-AR at Ser312 (third intracellular loop) to dictate recycling and resensitization itineraries of the internalized receptor.","method":"siRNA knockdown, co-immunoprecipitation, FRET microscopy, receptor recycling assays in HEK293 and SK-N-MC cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including FRET and functional siRNA rescue","pmids":["16940053"],"is_preprint":false},{"year":2006,"finding":"AKAP79 forms a receptosome with SAP97 at the type I PDZ motif (ESKV) of the β1-AR C-terminus; this scaffold targets PKA to phosphorylate β1-AR at Ser312, and the PDZ/scaffold complex is required for efficient receptor recycling.","method":"Co-immunoprecipitation, mutagenesis of PDZ motif, receptor recycling assays, PKA phosphorylation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — defined molecular interactions with functional receptor trafficking readout","pmids":["17170109"],"is_preprint":false},{"year":2007,"finding":"AKAP79/150 interacts directly with the CaV1.2 pore-forming subunit and co-targets PKA and calcineurin, conferring bidirectional regulation of L-type current amplitude; anchored calcineurin dominantly suppresses PKA enhancement. Additionally, AKAP79/150 is required for NFATc4 activation via local Ca²⁺ influx through L-type channels.","method":"Co-immunoprecipitation, electrophysiology in HEK293 and hippocampal neurons, NFAT reporter assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — direct protein interaction with bidirectional functional electrophysiology and NFAT transcription readout","pmids":["17640527"],"is_preprint":false},{"year":2008,"finding":"AKAP79/150 forms a signaling complex with TRPV1 through binding to a critical region in the TRPV1 C-terminus, and this complex scaffolds PKA, PKC, and calcineurin to mediate sensitization of TRPV1 by inflammatory mediators (bradykinin, PGE2); disruption of AKAP79/150 binding abrogates heat hyperalgesia.","method":"Co-immunoprecipitation, deletion mapping of TRPV1 C-terminal binding region, electrophysiology, in vivo hyperalgesia assay","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — direct binding site identification plus in vivo functional readout","pmids":["18701070"],"is_preprint":false},{"year":2008,"finding":"AKAP79 selectively enhances PKC-mediated phosphorylation of GluR1 at Ser831 by localizing PKC near the receptor via SAP97, shifting the dose-dependence for PKC modulation ~20-fold and making low PKC concentrations as effective as much higher CaMKII concentrations.","method":"Biochemical phosphorylation assays, electrophysiology in HEK293 cells, AKAP79-SAP97-GluR1 complex characterization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro phosphorylation assays combined with electrophysiology, quantitative dose-response analysis","pmids":["18305116"],"is_preprint":false},{"year":2010,"finding":"AKAP5 organizes a caveolin-3-associated signaling module in cardiomyocytes that clusters adenylyl cyclase 5/6, PKA, calcineurin, and a specific subpopulation of CaV1.2 L-type channels; this complex is essential for β-adrenergic stimulation of calcium transients and PKA phosphorylation of ryanodine receptors and phospholamban. In AKAP5 KO, AC5/6 is displaced from caveolin-3 T-tubule complexes.","method":"AKAP5 knockout mice, calcium imaging, electrophysiology, co-immunoprecipitation, phosphorylation assays","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout with multiple orthogonal functional readouts","pmids":["20671242"],"is_preprint":false},{"year":2010,"finding":"AKAP79 interacts with multiple adenylyl cyclase isoforms (AC5, AC6, AC9) via their N-terminal regions, with a reciprocal binding surface on AKAP79 at residues 77–108; loss of AKAP150 decreases AMPA receptor-associated AC activity in brain.","method":"Co-immunoprecipitation, FRET (intensity- and lifetime-based) in living cells, peptide competition, brain extracts from AKAP150 KO mice","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — FRET mapping plus genetic mouse model validation","pmids":["20231277"],"is_preprint":false},{"year":2010,"finding":"AKAP79 anchors a muscarinic-receptor-activated pool of PKC that phosphorylates the KCNQ2 subunit of M-channels to enhance neuronal excitability; AKAP79 also protects anchored PKC from certain ATP-competitive inhibitors, modifying the cellular pharmacology of PKC.","method":"Dual fluorescent imaging/patch-clamp, FRET-based kinase activity reporter (CKAR), electrophysiology, pharmacological inhibitor profiling","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 — simultaneous imaging and electrophysiology in living cells, novel pharmacological phenotype","pmids":["20188672"],"is_preprint":false},{"year":2010,"finding":"AKAP79/150 directly associates with Ca²⁺-stimulable adenylyl cyclase 8 (AC8) and limits the sensitivity of AC8 to intracellular Ca²⁺, as shown in HEK293 cells, pancreatic insulin-secreting cells, and hippocampal neurons.","method":"Co-immunoprecipitation, live-cell Ca²⁺ and cAMP imaging in multiple cell types","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — replicated in three independent cell types with live-cell imaging","pmids":["20410303"],"is_preprint":false},{"year":2010,"finding":"Ca²⁺/calmodulin disrupts AKAP79/150 interaction with KCNQ2–5 (but not KCNQ1) M-type channels at the plasma membrane, preventing AKAP79-mediated sensitization of these channels to muscarinic inhibition; AKAP79 associates with M1 and AT1 receptors and KCNQ2/3 channels as shown by TIRF/FRET.","method":"TIRF/FRET microscopy, perforated patch-clamp electrophysiology, KCNQ subunit mutagenesis (T553A), dominant-negative calmodulin","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — FRET plus electrophysiology with mutagenesis, subtype specificity established","pmids":["20147557"],"is_preprint":false},{"year":2010,"finding":"AKAP5 deletion in hippocampal and striatal neurons causes delocalization of PKA to dendritic shafts with increased binding to MAP2; the PKA-binding domain of AKAP5 is specifically required to maintain PKA near postsynaptic sites for synaptic plasticity and operant learning.","method":"AKAP5 KO and D36 (PKA-binding domain deletion) knock-in mice, electrophysiology, behavioral assays, immunofluorescence","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — genetic models with defined domain deletion, electrophysiology, and behavioral phenotyping","pmids":["20428246"],"is_preprint":false},{"year":2011,"finding":"AKAP79 dimerizes (stabilized by K328–K328 and K333–K333 cross-links) and, upon addition of Ca²⁺/CaM, assembles a 466-kDa complex comprising dimeric AKAP79 coordinating two RII homodimers, four PP2B heterodimers, and two CaM molecules; Ca²⁺/CaM binding generates a second interface for PP2B, activating anchored phosphatase.","method":"Native mass spectrometry, chemical cross-linking, quantitative biochemical reconstitution","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — native MS with reconstitution defines stoichiometry and activation mechanism","pmids":["21464287"],"is_preprint":false},{"year":2011,"finding":"Palmitoylation of AKAP79 at two N-terminal cysteines is required for targeting to lipid rafts in HEK293 cells; loss of palmitoylation excludes AKAP79 from rafts, alters membrane diffusion, and abolishes AKAP79-dependent regulation of SOCE-stimulated AC8 activity and PKA-dependent phosphorylation of raft proteins.","method":"Mutagenesis of palmitoylation cysteines, pharmacological depalmitoylation, sucrose density fractionation (lipid raft isolation), FRAP, AC activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — mutagenesis plus multiple biochemical and functional assays","pmids":["21771783"],"is_preprint":false},{"year":2011,"finding":"AKAP79/150 anchors PKA to regulate Kv4.2 (A-type K⁺ channel) surface expression in hippocampal neurons; the Kv4.2 C-terminal domain interacts with an internal region of AKAP79/150 overlapping its MAGUK-binding domain, and disrupting PKA anchoring decreases neuronal excitability while blocking calcineurin dephosphorylation increases excitability.","method":"Co-immunoprecipitation, surface biotinylation assay, patch-clamp electrophysiology, PKA anchoring disruption (Ht31 peptide)","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — direct interaction mapping with bidirectional functional electrophysiology readout","pmids":["21273417"],"is_preprint":false},{"year":2011,"finding":"AKAP79 is a novel PP1 regulatory subunit: it directly binds PP1 via a consensus FxxR/KxR/K motif in its first 44 amino acids (enhancing PP1 activity) and a second inhibitory domain at residues 150–250; AKAP79 inhibition of PP1 is substrate-dependent.","method":"Co-immunoprecipitation from rat brain, pulldown with purified proteins, PP1 activity assays, surface plasmon resonance, deletion mutagenesis","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro assay with purified proteins plus SPR and mutagenesis","pmids":["21561082"],"is_preprint":false},{"year":2012,"finding":"The IAIIIT anchoring motif in human AKAP79 (residues 337–343) binds the same surface of calcineurin as the PxIxIT recognition peptide of NFAT; higher-affinity AKAP–calcineurin interaction impairs NFAT activation by slowing calcineurin release and sequestering it at decoy sites, revealing an optimal affinity window for NFAT signaling.","method":"Structural analysis, mutagenesis of anchoring sequence, calcineurin binding assays, NFAT reporter assays in hippocampal neurons","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 — structural plus functional mutagenesis with neuronal NFAT activation assay","pmids":["22343722"],"is_preprint":false},{"year":2012,"finding":"AKAP79 recruits and scaffolds an AC8–AKAP79–PKA signaling complex; PKA phosphorylates AC8 at Ser112 to provide feedback inhibition of Ca²⁺-stimulated cAMP synthesis, reducing the on-rate of cAMP production during Ca²⁺ oscillations.","method":"Site-directed mutagenesis (Ser112), live-cell cAMP imaging during Ca²⁺ oscillations, co-immunoprecipitation","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis of phosphorylation site with live-cell functional imaging","pmids":["22976297"],"is_preprint":false},{"year":2012,"finding":"CaMKIIα phosphorylates a specific SAP97 splice variant (containing I3 and I5 inserts) to disrupt its interaction with AKAP79/150, thereby disengaging AKAP79/150 from regulating GluR1 AMPA receptors.","method":"Co-immunoprecipitation, in vitro and cell-based phosphorylation assays, GST pulldowns of splice variants, electrophysiology in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — splice-variant specific mechanism with in vitro phosphorylation and electrophysiology","pmids":["19858198"],"is_preprint":false},{"year":2012,"finding":"AKAP79/150 interacts with the neuronal calcium-binding protein caldendrin; caldendrin and calmodulin compete for a partially overlapping binding site on AKAP79 (B-domain), with different Ca²⁺ dependencies—calmodulin binds only with Ca²⁺ via a simple 1-step mechanism, while caldendrin uses an induced-fit mechanism and can bind independent of Ca²⁺.","method":"GST pulldown, surface plasmon resonance biosensor analysis, kinetic interaction modeling","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 1–2 — SPR with kinetic modeling defines mechanism and competition at molecular level","pmids":["22693956","22996592"],"is_preprint":false},{"year":2012,"finding":"AKAP79 modulates CaV1.2 L-type channel membrane targeting through relief of an autoinhibitory interaction between the channel's distal C-terminus and the II–III linker; the distal C-terminus of CaV1.2 directly interacts with AKAP79.","method":"Mutagenesis of polyproline domains, co-immunoprecipitation, channel membrane expression assay","journal":"Channels","confidence":"Medium","confidence_rationale":"Tier 2–3 — mechanistic model supported by mutagenesis and co-IP, single study","pmids":["22677788"],"is_preprint":false},{"year":2012,"finding":"AKAP79/150-mediated calcineurin–NFAT signaling drives activity-dependent transcriptional upregulation of KCNQ2/3 M-channels in hippocampal neurons; this requires Ca²⁺ influx through L-type channels and is absent in AKAP150⁻/⁻ mice after seizures.","method":"AKAP150 KO mice, in vivo seizure induction, KCNQ2/3 mRNA quantification, NFAT reporter assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with in vivo seizure model plus NFAT reporter","pmids":["23259949"],"is_preprint":false},{"year":2013,"finding":"The AKAP79–TRPV1 interaction is mediated by a region on AKAP79 between amino acids 326–336; a peptide from this domain inhibits TRPV1 sensitization in vitro, and a cell-penetrant TAT-linked version inhibits inflammatory hyperalgesia in mice without affecting basal pain thresholds.","method":"FRET, co-immunoprecipitation, TRPV1 membrane trafficking assay, in vivo hyperalgesia assay","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — direct mapping of binding site with in vivo functional validation","pmids":["23699529"],"is_preprint":false},{"year":2013,"finding":"AKAP5 anchoring of adenylyl cyclase (in addition to PKA) is required for β-adrenergic stimulation of GluA1 Ser845 phosphorylation and for LTP induced by 5-Hz θ-rhythm stimulation; AKAP5 KO (lacking both AC and PKA anchoring) produces much greater impairment than D36 (PKA-binding deletion only).","method":"AKAP5 KO and D36 knock-in mice, phosphorylation assays, hippocampal slice electrophysiology (LTP), β-adrenergic stimulation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic dissection of AC vs PKA anchoring with LTP readout","pmids":["23649627"],"is_preprint":false},{"year":2014,"finding":"AKAP5-anchored PKA controls GluA1 S845 phosphorylation and AMPAR surface trafficking during homeostatic scaling; PKA is lost from synapses during scaling down and enriched during scaling up; knockdown of AKAP5 blocks scaling up.","method":"siRNA knockdown of AKAP5, FRET-based PKA activity reporters, GluA1 S845 phosphorylation assays, surface AMPAR assays, GluA1 S845 knockin mice","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, genetic knockin validation","pmids":["25451194"],"is_preprint":false},{"year":2015,"finding":"The recycling endosome-resident palmitoyl acyltransferase DHHC2 interacts with and palmitoylates AKAP79/150, targeting it to recycling endosomes in dendrites; DHHC2 knockdown disrupts recycling endosome exocytosis, spine enlargement, AKAP recruitment to spines, and LTP-induced AMPAR synaptic potentiation.","method":"RNAi knockdown, palmitoylation assay, dendritic exocytosis assay, spine morphology, AMPAR synaptic current recordings, rescue with lipidated AKAP mutant","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — identifies the palmitoyl transferase (DHHC2) and validates with rescue experiment","pmids":["25589740"],"is_preprint":false},{"year":2015,"finding":"AKAP79-anchored PKA phosphorylates STIM1 at T389 in the plasma membrane pool; this phosphorylation is specifically required for activation of store-independent ARC channels (but actually inhibits STIM1-dependent CRAC channel activation), demonstrating selective regulation of two co-existing Orai channel types.","method":"Site-directed mutagenesis (T389A), co-immunoprecipitation, patch-clamp electrophysiology, knockdown of AKAP79","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1–2 — phosphorylation site mutagenesis with functional electrophysiological readout","pmids":["25504574"],"is_preprint":false},{"year":2017,"finding":"Intrinsic disorder in AKAP79 produces an ensemble of AKAP79–PP2B configurations; a short linear motif (residues 337–343) is the sole PP2B-anchoring determinant; Ca²⁺/CaM engagement of additional surfaces (including Leu-Lys-Ile-Pro, residues 125–128) condenses configurational variants and fine-tunes phosphatase activity and cyclosporin sensitivity.","method":"Negative-stain electron microscopy, chemical cross-linking, live-cell fluorescent activity sensors (NFAT translocation), site-directed mutagenesis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — structural EM combined with mutagenesis and live-cell functional reporters","pmids":["28967377"],"is_preprint":false},{"year":2017,"finding":"LTD-induced synaptic removal of AKAP79/150 requires CaMKII activity and depalmitoylation of two N-terminal Cys residues; CaMKII phosphorylates AKAP79/150's N-terminal polybasic domain (inhibiting F-actin association) preferentially via autonomous (Thr286-autophosphorylated) CaMKII; Ca²⁺/CaM binding to the substrate sites protects them from phosphorylation in the presence of strong LTP stimuli, providing stimulus-selective regulation.","method":"CaMKII inhibitors and knockout, LTD induction in hippocampal neurons, palmitoylation assay, spine morphology, actin-binding assay, phospho-site mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection with multiple methods, identifies depalmitoylation as primary mechanism over direct phosphorylation","pmids":["29196604"],"is_preprint":false},{"year":2019,"finding":"AKAP79 recruits the transcription factor NFAT via a C-terminal leucine-zipper (LZ) domain, forming a direct AKAP79–NFAT complex at the plasma membrane; this LZ-mediated NFAT recruitment (not the LTCC–AKAP interaction per se) is required for depolarization-induced NFAT signaling in hippocampal neurons.","method":"RNAi knockdown + replacement with LZ-deletion mutant, co-immunoprecipitation, FRET, Ca²⁺ imaging, FRAP, fluorescence correlation spectroscopy, electrophysiology","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — multiple imaging and electrophysiological methods with defined domain mutant","pmids":["31091162"],"is_preprint":false},{"year":2020,"finding":"AKAP5 organizes a nanocomplex containing P2Y11/P2Y11-like receptors, AC5, PKA, and CaV1.2 at the plasma membrane of arterial myocytes; disruption of AKAP5 blocks glucose- and P2Y11-induced cAMP synthesis, CaV1.2 potentiation, and vasoconstriction.","method":"AKAP5 KO mice, calcium imaging, proximity ligation assay, TIRF microscopy, patch-clamp, myography","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple functional vascular readouts","pmids":["33082339"],"is_preprint":false},{"year":2020,"finding":"STIM2 recruits Orai1/STIM1 to ER–PM junctions and promotes assembly with AKAP79 to couple Orai1 channel function to NFAT1 activation; STIM2 polybasic domain mediates this assembly. Loss of STIM2 impairs NFAT1 activation and Orai1–AKAP79 association without significantly affecting global Ca²⁺.","method":"Co-immunoprecipitation, knockdown, STIM1ΔK mutant, NFAT1 translocation assay, Ca²⁺ imaging","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic tools with defined molecular requirements","pmids":["32601188"],"is_preprint":false},{"year":2021,"finding":"The N-terminus of Orai1 (lacking in Orai2, Orai3, and short Orai1) contains an AKAP79-interaction site required for excitation-transcription coupling; NMR reveals a compact, proline-driven structure at this site; disrupting Orai1–AKAP79 interaction suppresses cytokine production without affecting other Orai1 functions.","method":"NMR structural analysis, co-immunoprecipitation, NFAT1 translocation assay, cytokine production assay, Orai isoform comparison","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — NMR structure with functional validation in intact cells","pmids":["33941685"],"is_preprint":false},{"year":2021,"finding":"AKAP79 increases the rate of calcineurin dephosphorylation of type II PKA regulatory (RII) subunits by ~10-fold, enabling calcineurin to suppress PKA activity without altering cAMP levels by increasing catalytic subunit capture rate; kinetic modeling and hippocampal neuron experiments indicate this contributes to LTD.","method":"In vitro phosphatase activity assay, fluorescent PKA activity reporter, kinetic modeling, hippocampal neuron electrophysiology","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution with kinetic modeling plus neuronal functional validation","pmids":["34612814"],"is_preprint":false},{"year":2021,"finding":"AKAP79/150 coordinates leptin-induced PKA signaling at the cell membrane to regulate KATP channel trafficking in pancreatic β-cells; AKAP79/150 knockdown abolishes leptin-induced membrane PKA activity increases; disrupting PP2B anchoring to AKAP79/150 elevates basal PKA signaling and increases surface KATP channels.","method":"FRET-based PKA reporters, siRNA knockdown, KATP channel surface assay, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — FRET reporters with genetic knockdown and domain-specific disruption","pmids":["33617875"],"is_preprint":false},{"year":2010,"finding":"AKAP79/150 pre-assembled with RXFP1 (relaxin receptor), AC2, β-arrestin 2, and PDE4D3 forms a constitutively active signalosome; AC2 is functionally coupled to RXFP1 through AKAP79 binding to helix 8 of RXFP1; PKA-activated PDE4D3 (via β-arrestin 2 on Ser704 of RXFP1) provides tonic opposition to cAMP, enabling sub-picomolar relaxin signaling.","method":"Co-immunoprecipitation, cAMP biosensors in single cells, deletion mapping, mutagenesis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — single-cell biosensors with molecular mapping of complex components","pmids":["20664520"],"is_preprint":false},{"year":2019,"finding":"AKAP79-anchored PKC phosphorylates GluA1 at Ser831, which is sufficient to drive appearance of Ca²⁺-permeable (GluA2-lacking) AMPARs; other AKAP79 signaling components (PKA/calcineurin) and C-terminal phosphorylation sites play a permissive/limiting role.","method":"Electrophysiology (I-V relationships), mutagenesis of GluA1 phosphorylation sites, AKAP79 deletion mutants in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — defined phosphorylation site with electrophysiological readout of receptor Ca²⁺ permeability","pmids":["30737285"],"is_preprint":false}],"current_model":"AKAP5 (AKAP79/150) is a multivalent postsynaptic scaffold protein that simultaneously anchors PKA, calcineurin (PP2B), PKC, adenylyl cyclases (AC5/6/8), and the transcription factor NFAT at the plasma membrane via distinct binding domains; membrane targeting is mediated by N-terminal polybasic regions that bind PIP2 and are regulated by palmitoylation (via DHHC2), phosphorylation, and Ca²⁺/calmodulin, while the scaffold organizes bidirectional phosphoregulation of CaV1.2 channels, TRPV1, AMPA receptors (GluA1 Ser831/Ser845), KCNQ M-channels, Kv4.2, and adrenergic receptors, and couples local Ca²⁺ entry through Orai1 and L-type channels to calcineurin-dependent NFAT activation."},"narrative":{"teleology":[{"year":1993,"claim":"Identification of the membrane-targeting and PKA-RII-binding domains established that AKAP5 uses physically separable determinants for subcellular localization versus kinase anchoring.","evidence":"Deletion and scanning mutagenesis of bovine AKAP75 in HEK293 cells with RII overlay assay","pmids":["8509414"],"confidence":"High","gaps":["Lipid specificity of membrane-targeting domains not yet defined","Structure of the RII-binding helix not resolved"]},{"year":1996,"claim":"Demonstration that a single scaffold simultaneously binds PKA, calcineurin, and PKC at distinct sites established the multivalent signaling-hub concept for AKAPs.","evidence":"Deletion analysis, co-immunoprecipitation, and immunofluorescence in hippocampal neurons","pmids":["8599116"],"confidence":"High","gaps":["Stoichiometry of multi-enzyme assembly unknown","Functional consequences for substrates not yet tested"]},{"year":1997,"claim":"Discovery that Ca²⁺/calmodulin competes with PKC for the same N-terminal AKAP79 region revealed a Ca²⁺-dependent switch controlling which enzyme occupies the scaffold.","evidence":"Calmodulin binding assays and PKC activity assays from postsynaptic density preparations","pmids":["9202019"],"confidence":"High","gaps":["In vivo dynamics of CaM/PKC competition not measured","Whether CaM displaces PKC during synaptic activity unknown"]},{"year":1998,"claim":"Mapping PIP2-dependent membrane anchoring to three polybasic N-terminal regions and showing their disruption by phosphorylation and Ca²⁺/CaM established a regulated membrane-release mechanism for the scaffold.","evidence":"GFP targeting assays, lipid vesicle binding, subcellular fractionation in HEK293 and cortical neurons","pmids":["9545238"],"confidence":"High","gaps":["Identity of palmitoylating enzyme unknown at this time","Whether membrane release occurs during synaptic plasticity not shown"]},{"year":1999,"claim":"Elucidation that AKAP79 inhibits PKC by displacing its pseudosubstrate domain via R39/R40 contacts explained how the scaffold holds PKC in an inactive-but-releasable state.","evidence":"In vitro kinase assays, limited proteolysis, and site-directed mutagenesis with multiple PKC isoforms","pmids":["10510312"],"confidence":"High","gaps":["Structural basis of pseudosubstrate displacement not resolved","Release kinetics in cells unknown"]},{"year":2002,"claim":"A series of studies established that AKAP79 connects to AMPA receptors via SAP97 to mediate PKA-dependent GluA1 Ser845 phosphorylation and calcineurin-dependent current rundown, providing a molecular mechanism for bidirectional synaptic plasticity and a direct role in LTD-like processes.","evidence":"Co-immunoprecipitation, electrophysiology in HEK293 and hippocampal neurons, FRET microscopy showing PKA-RII and calcineurin within ~50 Å on the scaffold","pmids":["11943807","12354762","12507994"],"confidence":"High","gaps":["Whether this complex operates at single identified synapses in vivo not shown","Relative contribution of PP2B versus PP1 in LTD unclear"]},{"year":2002,"claim":"Demonstration that AKAP79 controls CaV1.2 surface expression via the channel's II–III loop polyproline motif revealed a PKA-independent scaffolding function for channel trafficking.","evidence":"Extracellular epitope tagging, single-channel and whole-cell electrophysiology","pmids":["12114507"],"confidence":"High","gaps":["Mechanism by which AKAP79 relieves autoinhibition of CaV1.2 not fully resolved","In vivo cardiac consequences not tested at this point"]},{"year":2005,"claim":"Identification of AKAP79 as the specific AKAP that provides PKA for β2-AR Gs-to-Gi switching, opposed by PDE4D5/β-arrestin, placed AKAP5 at the center of GPCR signaling bias.","evidence":"Isoform-selective siRNA, PKA activity assays, ERK phosphorylation in HEK293B2 cells","pmids":["16030021"],"confidence":"High","gaps":["Whether this mechanism operates in cardiomyocytes or neurons not tested","Direct structural interface between AKAP79 and β2-AR not mapped"]},{"year":2006,"claim":"Showing that AKAP79–SAP97 forms a receptosome with β1-AR where PKA phosphorylation at Ser312 dictates recycling defined the scaffold's role in receptor resensitization.","evidence":"siRNA, FRET, receptor recycling assays, PDZ motif mutagenesis in HEK293 and SK-N-MC cells","pmids":["16940053","17170109"],"confidence":"High","gaps":["Whether recycling pathway is conserved across all β1-AR-expressing tissues unknown"]},{"year":2007,"claim":"Co-targeting of PKA and calcineurin to CaV1.2 by AKAP79/150 was shown to produce bidirectional L-type current regulation with dominant calcineurin suppression, and to couple local Ca²⁺ entry to NFAT activation—linking channel regulation to gene expression.","evidence":"Co-immunoprecipitation, electrophysiology in HEK293 and hippocampal neurons, NFAT reporter assays","pmids":["17640527"],"confidence":"High","gaps":["Whether NFAT isoform selectivity exists in this complex not addressed","Distance constraints between channel pore and calcineurin active site unknown"]},{"year":2008,"claim":"Mapping the AKAP79–TRPV1 interaction to the TRPV1 C-terminus and demonstrating that the complex mediates inflammatory heat hyperalgesia in vivo extended the scaffold's role to nociception.","evidence":"Deletion mapping, electrophysiology, in vivo hyperalgesia assays","pmids":["18701070"],"confidence":"High","gaps":["Structural basis of TRPV1–AKAP79 binding not resolved","Contribution of individual enzymes (PKA vs PKC vs calcineurin) to sensitization not fully parsed"]},{"year":2010,"claim":"Multiple 2010 studies collectively established that AKAP5 anchors adenylyl cyclases (AC5/6/8/9) via residues 77–108, organizes them in caveolin-3 complexes in cardiomyocytes for β-adrenergic calcium transients, limits AC8 Ca²⁺ sensitivity, and anchors PKC to KCNQ2 M-channels—demonstrating the scaffold coordinates both cAMP production and ion channel modulation.","evidence":"AKAP5 KO mice, FRET in living cells, calcium imaging, electrophysiology, AC activity assays in brain extracts","pmids":["20671242","20231277","20410303","20188672","20147557"],"confidence":"High","gaps":["Whether AC isoform selectivity differs between cell types not resolved","Structural basis for AC N-terminal interaction with AKAP79 unknown"]},{"year":2010,"claim":"Genetic dissection using AKAP5 KO versus D36 (PKA-binding-deleted) knock-in mice proved that PKA anchoring by AKAP5 is specifically required for postsynaptic PKA localization, synaptic plasticity, and operant learning.","evidence":"KO and domain-deletion knock-in mice, electrophysiology, immunofluorescence, behavioral assays","pmids":["20428246"],"confidence":"High","gaps":["Relative contribution of calcineurin-anchoring versus PKA-anchoring to learning not separated in this study"]},{"year":2011,"claim":"Native mass spectrometry revealed AKAP79 dimerizes and assembles a 466-kDa complex with defined stoichiometry (2 AKAP79 : 2 RII dimers : 4 PP2B heterodimers : 2 CaM), where Ca²⁺/CaM generates a second PP2B interface to activate anchored phosphatase.","evidence":"Native mass spectrometry, chemical cross-linking, quantitative reconstitution","pmids":["21464287"],"confidence":"High","gaps":["How dimerization interfaces relate to substrate access unknown","Whether dimeric vs monomeric forms differ in cellular context not tested"]},{"year":2011,"claim":"Identification of N-terminal palmitoylation sites as required for lipid-raft targeting, AC8 regulation, and raft-associated PKA signaling established lipid modification as a major determinant of scaffold compartmentalization.","evidence":"Palmitoylation-site mutagenesis, FRAP, lipid-raft fractionation, AC activity assays in HEK293 cells","pmids":["21771783"],"confidence":"High","gaps":["Identity of palmitoyl acyltransferase not determined at this stage"]},{"year":2012,"claim":"The calcineurin-anchoring motif IAIIIT (residues 337–343) was shown to occupy the same PxIxIT surface on calcineurin as NFAT, establishing an optimal-affinity window where too-tight AKAP–calcineurin binding sequesters calcineurin away from NFAT substrates.","evidence":"Structural analysis, mutagenesis of anchoring sequence, NFAT reporter assays in hippocampal neurons","pmids":["22343722"],"confidence":"High","gaps":["Full atomic-resolution structure of AKAP79–calcineurin complex not available","Whether affinity tuning is dynamically regulated in vivo unknown"]},{"year":2012,"claim":"AKAP79/150–calcineurin–NFAT signaling was shown to drive activity-dependent transcriptional upregulation of KCNQ2/3 after seizures, requiring L-type Ca²⁺ influx and absent in AKAP150 KO mice, establishing a gene-expression feedback loop from channel to scaffold to transcription.","evidence":"AKAP150 KO mice, in vivo seizure induction, KCNQ2/3 mRNA quantification, NFAT reporter assays","pmids":["23259949"],"confidence":"High","gaps":["Full set of NFAT target genes regulated by AKAP150 not identified","Whether this loop operates in non-seizure physiological activity unknown"]},{"year":2015,"claim":"Identification of DHHC2 as the palmitoyl acyltransferase that palmitoylates AKAP79/150 on recycling endosomes, and demonstration that this is required for LTP-induced spine delivery and AMPAR potentiation, completed the palmitoylation-dependent trafficking mechanism.","evidence":"RNAi knockdown, palmitoylation assay, exocytosis assay, spine morphology, AMPAR recordings, rescue with lipidated AKAP mutant","pmids":["25589740"],"confidence":"High","gaps":["Whether depalmitoylation during LTD uses a specific thioesterase not identified","Kinetics of palmitoylation cycling at single spines unknown"]},{"year":2017,"claim":"Negative-stain EM and mutagenesis revealed that intrinsic disorder in AKAP79 allows an ensemble of configurations with calcineurin; Ca²⁺/CaM engagement of additional motifs (including LKIP at residues 125–128) condenses the ensemble, fine-tuning phosphatase activity and drug sensitivity.","evidence":"Negative-stain EM, chemical cross-linking, NFAT translocation reporters, mutagenesis","pmids":["28967377"],"confidence":"High","gaps":["High-resolution structure of the full-length complex still lacking","How ensemble condensation changes substrate selectivity in cells not measured"]},{"year":2017,"claim":"CaMKII was shown to drive LTD-associated synaptic removal of AKAP79/150 by promoting depalmitoylation and phosphorylating the N-terminal polybasic domain to inhibit F-actin binding, with Ca²⁺/CaM protecting these sites during LTP-type stimuli—explaining stimulus-selective scaffold trafficking.","evidence":"CaMKII inhibitors/KO, LTD induction, palmitoylation assay, actin-binding assay, phospho-site mutagenesis in hippocampal neurons","pmids":["29196604"],"confidence":"High","gaps":["Specific CaMKII phospho-sites on AKAP150 not all mapped","Whether CaM protection is quantitatively sufficient in all stimulus regimes unclear"]},{"year":2019,"claim":"Demonstration that AKAP79 recruits NFAT via a C-terminal leucine zipper (rather than through the LTCC interaction alone) resolved how the scaffold pre-positions NFAT near local Ca²⁺ sources for excitation–transcription coupling.","evidence":"LZ-deletion mutant replacement, co-IP, FRET, Ca²⁺ imaging, FCS in hippocampal neurons","pmids":["31091162"],"confidence":"High","gaps":["Whether the LZ domain recruits other transcription factors not tested","Structural basis of AKAP79 LZ–NFAT interaction not resolved"]},{"year":2020,"claim":"AKAP5 was shown to organize a P2Y11–AC5–PKA–CaV1.2 nanocomplex in arterial myocytes required for glucose-induced vasoconstriction, extending the scaffold's physiological roles to vascular tone regulation.","evidence":"AKAP5 KO mice, proximity ligation assay, TIRF, patch-clamp, myography","pmids":["33082339"],"confidence":"High","gaps":["Whether this complex is altered in diabetes not tested","Precise stoichiometry in vascular smooth muscle unknown"]},{"year":2021,"claim":"NMR structural analysis of the Orai1 N-terminus revealed a compact proline-driven structure mediating AKAP79 binding that is unique to full-length Orai1, and disrupting this interface suppressed NFAT-dependent cytokine production without affecting other Orai1 functions—establishing a selective excitation–transcription coupling mechanism.","evidence":"NMR, co-IP, NFAT translocation, cytokine assay, Orai isoform comparison","pmids":["33941685"],"confidence":"High","gaps":["Whether pharmacological disruption of Orai1–AKAP79 is therapeutically viable not tested","Full interface structure at atomic resolution not available"]},{"year":2021,"claim":"Reconstitution showed AKAP79 accelerates calcineurin-mediated RII dephosphorylation ~10-fold, enabling calcineurin to suppress PKA activity without changing cAMP—establishing a cAMP-independent mechanism for PKA inhibition during LTD.","evidence":"In vitro phosphatase assay, fluorescent PKA activity reporter, kinetic modeling, hippocampal neuron electrophysiology","pmids":["34612814"],"confidence":"High","gaps":["Whether this mechanism contributes to non-neuronal AKAP5 functions not tested","Relative importance versus direct catalytic subunit inhibition not quantified in vivo"]},{"year":null,"claim":"High-resolution structural determination of the full-length AKAP79 dimer in complex with its enzyme cohort, and understanding how the intrinsically disordered scaffold selects among multiple substrates in a stimulus-specific manner, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No atomic-resolution structure of full-length AKAP79 or its multi-enzyme complexes","Mechanisms governing substrate selectivity among co-anchored enzymes in physiological settings largely inferred from reconstitution","Whether AKAP5 mutations contribute to human neurological or cardiovascular disease not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,11,25]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,8,28,46]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3,11,26,43]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[38]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,13,14,16,48]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[10,24,27,34,37]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[9,16,19,43]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,29,34,42]}],"complexes":["AKAP79–PKA-RII–calcineurin ternary complex","AKAP79–SAP97–GluA1 complex","AKAP79–AC5/6/8–PKA signalosome","AKAP79–CaV1.2–PKA–calcineurin complex"],"partners":["PRKAR2A","PPP3CA","DLG1","ADCY8","ADCY5","CACNA1C","TRPV1","ORAI1"],"other_free_text":[]},"mechanistic_narrative":"AKAP5 (AKAP79 in human, AKAP150 in rodents) is a multivalent scaffold protein that orchestrates bidirectional phospho-signaling at the plasma membrane by simultaneously anchoring PKA, calcineurin (PP2B), PKC, PP1, and adenylyl cyclases (AC5/6/8/9) through distinct, mapped binding domains, thereby coordinating the phosphorylation state of ion channels, receptors, and transcription factors in neurons, cardiomyocytes, smooth muscle, and pancreatic β-cells [PMID:8599116, PMID:21561082, PMID:20231277]. Membrane targeting depends on three N-terminal polybasic regions that bind PIP2, with dynamic regulation by palmitoylation (via DHHC2), Ca²⁺/calmodulin displacement, and CaMKII phosphorylation controlling stimulus-selective trafficking into and out of dendritic spines during LTP and LTD [PMID:9545238, PMID:25589740, PMID:29196604]. The scaffold assembles as a dimer that positions PKA-RII and calcineurin within ~50 Å, enabling calcineurin to accelerate RII dephosphorylation ~10-fold and thereby suppress PKA without changing cAMP, while PKC anchored to the same complex phosphorylates substrates such as GluA1 Ser831 and KCNQ2 to control AMPA receptor calcium permeability and M-channel excitability [PMID:12507994, PMID:34612814, PMID:20188672, PMID:30737285]. AKAP5 also recruits NFAT via a C-terminal leucine zipper and couples local Ca²⁺ entry through CaV1.2 and Orai1 to calcineurin-dependent NFAT nuclear translocation, linking channel activity to gene expression programs including activity-dependent KCNQ2/3 upregulation [PMID:31091162, PMID:33941685, PMID:23259949]."},"prefetch_data":{"uniprot":{"accession":"P24588","full_name":"A-kinase anchor protein 5","aliases":["A-kinase anchor protein 79 kDa","AKAP 79","H21","cAMP-dependent protein kinase regulatory subunit II high affinity-binding protein"],"length_aa":427,"mass_kda":47.1,"function":"Multivalent scaffold protein that anchors the cAMP-dependent protein kinase/PKA to cytoskeletal and/or organelle-associated proteins, targeting the signal carried by cAMP to specific intracellular effectors (PubMed:1512224). Association with the beta2-adrenergic receptor (beta2-AR) not only regulates beta2-AR signaling pathway, but also the activation by PKA by switching off the beta2-AR signaling cascade. Plays a role in long term synaptic potentiation by regulating protein trafficking from the dendritic recycling endosomes to the plasma membrane and controlling both structural and functional plasticity at excitatory synapses (PubMed:25589740). In hippocampal pyramidal neurons, recruits KCNK2/TREK-1 channel at postsynaptic dense bodies microdomains and converts it to a leak channel no longer sensitive to stimulation by arachidonic acid, acidic pH or mechanical stress, nor inhibited by Gq-coupled receptors but still under the negative control of Gs-coupled receptors (By similarity). Associates with ORAI1 pore-forming subunit of CRAC channels in Ca(2+) signaling microdomains where it recruits NFATC2/NFAT1 and couples store-operated Ca(2+) influx to calmodulin and calcineurin signaling and activation of NFAT-dependent transcriptional responses (PubMed:33941685)","subcellular_location":"Postsynaptic recycling endosome membrane; Cell projection, dendrite; Postsynaptic cell membrane","url":"https://www.uniprot.org/uniprotkb/P24588/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AKAP5","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PRKACA","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/AKAP5","total_profiled":1310},"omim":[{"mim_id":"616427","title":"A-KINASE ANCHOR INHIBITOR 1; AKAIN1","url":"https://www.omim.org/entry/616427"},{"mim_id":"604688","title":"A-KINASE ANCHOR PROTEIN 5; AKAP5","url":"https://www.omim.org/entry/604688"},{"mim_id":"603870","title":"CORE-BINDING FACTOR, ALPHA SUBUNIT 2, TRANSLOCATED TO, 3; CBFA2T3","url":"https://www.omim.org/entry/603870"},{"mim_id":"114105","title":"PROTEIN PHOSPHATASE 3, CATALYTIC SUBUNIT, ALPHA ISOFORM; PPP3CA","url":"https://www.omim.org/entry/114105"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":17.6}],"url":"https://www.proteinatlas.org/search/AKAP5"},"hgnc":{"alias_symbol":["AKAP75","AKAP79"],"prev_symbol":[]},"alphafold":{"accession":"P24588","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P24588","model_url":"https://alphafold.ebi.ac.uk/files/AF-P24588-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P24588-F1-predicted_aligned_error_v6.png","plddt_mean":54.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AKAP5","jax_strain_url":"https://www.jax.org/strain/search?query=AKAP5"},"sequence":{"accession":"P24588","fasta_url":"https://rest.uniprot.org/uniprotkb/P24588.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P24588/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P24588"}},"corpus_meta":[{"pmid":"8599116","id":"PMC_8599116","title":"Coordination of three signaling enzymes by AKAP79, a mammalian scaffold protein.","date":"1996","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/8599116","citation_count":479,"is_preprint":false},{"pmid":"17640527","id":"PMC_17640527","title":"AKAP79/150 anchoring of calcineurin controls neuronal L-type Ca2+ channel activity and nuclear signaling.","date":"2007","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/17640527","citation_count":284,"is_preprint":false},{"pmid":"18701070","id":"PMC_18701070","title":"Proinflammatory mediators modulate the heat-activated ion channel TRPV1 via the scaffolding protein AKAP79/150.","date":"2008","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/18701070","citation_count":217,"is_preprint":false},{"pmid":"9545238","id":"PMC_9545238","title":"Membrane-targeting sequences on AKAP79 bind phosphatidylinositol-4, 5-bisphosphate.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9545238","citation_count":204,"is_preprint":false},{"pmid":"11943807","id":"PMC_11943807","title":"Regulation of GluR1 by the A-kinase anchoring protein 79 (AKAP79) signaling complex shares properties with long-term depression.","date":"2002","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/11943807","citation_count":183,"is_preprint":false},{"pmid":"16030021","id":"PMC_16030021","title":"RNA silencing identifies PDE4D5 as the functionally relevant cAMP phosphodiesterase interacting with beta arrestin to control the protein kinase A/AKAP79-mediated switching of the beta2-adrenergic receptor to activation of ERK in HEK293B2 cells.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16030021","citation_count":169,"is_preprint":false},{"pmid":"20671242","id":"PMC_20671242","title":"Sympathetic stimulation of adult cardiomyocytes requires association of AKAP5 with a subpopulation of L-type calcium channels.","date":"2010","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/20671242","citation_count":140,"is_preprint":false},{"pmid":"11278469","id":"PMC_11278469","title":"Regulation of membrane targeting of the G protein-coupled receptor kinase 2 by protein kinase A and its anchoring protein AKAP79.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11278469","citation_count":134,"is_preprint":false},{"pmid":"25451194","id":"PMC_25451194","title":"PKA-GluA1 coupling via AKAP5 controls AMPA receptor phosphorylation and cell-surface targeting during bidirectional homeostatic plasticity.","date":"2014","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/25451194","citation_count":132,"is_preprint":false},{"pmid":"22343722","id":"PMC_22343722","title":"Balanced interactions of calcineurin with AKAP79 regulate Ca2+-calcineurin-NFAT signaling.","date":"2012","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22343722","citation_count":129,"is_preprint":false},{"pmid":"12354762","id":"PMC_12354762","title":"Mapping the protein phosphatase-2B anchoring site on AKAP79. Binding and inhibition of phosphatase activity are mediated by residues 315-360.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12354762","citation_count":124,"is_preprint":false},{"pmid":"12114507","id":"PMC_12114507","title":"Trafficking of L-type calcium channels mediated by the postsynaptic scaffolding protein AKAP79.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12114507","citation_count":112,"is_preprint":false},{"pmid":"10878251","id":"PMC_10878251","title":"AKAP79 and the evolution of the AKAP model.","date":"2000","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/10878251","citation_count":112,"is_preprint":false},{"pmid":"12507994","id":"PMC_12507994","title":"Imaging kinase--AKAP79--phosphatase scaffold complexes at the plasma membrane in living cells using FRET microscopy.","date":"2002","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/12507994","citation_count":109,"is_preprint":false},{"pmid":"9202019","id":"PMC_9202019","title":"Regulation of the AKAP79-protein kinase C interaction by Ca2+/Calmodulin.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9202019","citation_count":99,"is_preprint":false},{"pmid":"20188672","id":"PMC_20188672","title":"Interaction with AKAP79 modifies the cellular pharmacology of PKC.","date":"2010","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/20188672","citation_count":96,"is_preprint":false},{"pmid":"20231277","id":"PMC_20231277","title":"AKAP79 interacts with multiple adenylyl cyclase (AC) isoforms and scaffolds AC5 and -6 to alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20231277","citation_count":95,"is_preprint":false},{"pmid":"8509414","id":"PMC_8509414","title":"Characterization of distinct tethering and intracellular targeting domains in AKAP75, a protein that links cAMP-dependent protein kinase II beta to the cytoskeleton.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8509414","citation_count":79,"is_preprint":false},{"pmid":"21464287","id":"PMC_21464287","title":"Architecture and dynamics of an A-kinase anchoring protein 79 (AKAP79) signaling complex.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21464287","citation_count":78,"is_preprint":false},{"pmid":"10510312","id":"PMC_10510312","title":"Mechanism of A-kinase-anchoring protein 79 (AKAP79) and protein kinase C interaction.","date":"1999","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10510312","citation_count":75,"is_preprint":false},{"pmid":"21771783","id":"PMC_21771783","title":"Palmitoylation targets AKAP79 protein to lipid rafts and promotes its regulation of calcium-sensitive adenylyl cyclase type 8.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21771783","citation_count":74,"is_preprint":false},{"pmid":"20428246","id":"PMC_20428246","title":"Mutations in AKAP5 disrupt dendritic signaling complexes and lead to electrophysiological and behavioral phenotypes in mice.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20428246","citation_count":73,"is_preprint":false},{"pmid":"23259949","id":"PMC_23259949","title":"Activity-dependent transcriptional regulation of M-Type (Kv7) K(+) channels by AKAP79/150-mediated NFAT actions.","date":"2012","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/23259949","citation_count":72,"is_preprint":false},{"pmid":"9765270","id":"PMC_9765270","title":"AKAP79 inhibits calcineurin through a site distinct from the immunophilin-binding region.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9765270","citation_count":72,"is_preprint":false},{"pmid":"16940053","id":"PMC_16940053","title":"AKAP79-mediated targeting of the cyclic AMP-dependent protein kinase to the beta1-adrenergic receptor promotes recycling and functional resensitization of the receptor.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16940053","citation_count":71,"is_preprint":false},{"pmid":"20664520","id":"PMC_20664520","title":"Sub-picomolar relaxin signalling by a pre-assembled RXFP1, AKAP79, AC2, beta-arrestin 2, PDE4D3 complex.","date":"2010","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/20664520","citation_count":67,"is_preprint":false},{"pmid":"20410303","id":"PMC_20410303","title":"AKAP79/150 interacts with AC8 and regulates Ca2+-dependent cAMP synthesis in pancreatic and neuronal systems.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20410303","citation_count":66,"is_preprint":false},{"pmid":"17170109","id":"PMC_17170109","title":"Assembly of an SAP97-AKAP79-cAMP-dependent protein kinase scaffold at the type 1 PSD-95/DLG/ZO1 motif of the human beta(1)-adrenergic receptor generates a receptosome involved in receptor recycling and networking.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17170109","citation_count":65,"is_preprint":false},{"pmid":"25589740","id":"PMC_25589740","title":"The palmitoyl acyltransferase DHHC2 regulates recycling endosome exocytosis and synaptic potentiation through palmitoylation of AKAP79/150.","date":"2015","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25589740","citation_count":61,"is_preprint":false},{"pmid":"23649627","id":"PMC_23649627","title":"Adenylyl cyclase anchoring by a kinase anchor protein AKAP5 (AKAP79/150) is important for postsynaptic β-adrenergic signaling.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23649627","citation_count":58,"is_preprint":false},{"pmid":"11287423","id":"PMC_11287423","title":"Targeting of an A kinase-anchoring protein, AKAP79, to an inwardly rectifying potassium channel, Kir2.1.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11287423","citation_count":56,"is_preprint":false},{"pmid":"20147557","id":"PMC_20147557","title":"Ca2+/calmodulin disrupts AKAP79/150 interactions with KCNQ (M-Type) K+ channels.","date":"2010","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20147557","citation_count":53,"is_preprint":false},{"pmid":"24962572","id":"PMC_24962572","title":"G protein-coupled receptor 30 (GPR30) forms a plasma membrane complex with membrane-associated guanylate kinases (MAGUKs) and protein kinase A-anchoring protein 5 (AKAP5) that constitutively inhibits cAMP production.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24962572","citation_count":53,"is_preprint":false},{"pmid":"21562284","id":"PMC_21562284","title":"AKAP79/150 signal complexes in G-protein modulation of neuronal ion channels.","date":"2011","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21562284","citation_count":50,"is_preprint":false},{"pmid":"33941685","id":"PMC_33941685","title":"The N terminus of Orai1 couples to the AKAP79 signaling complex to drive NFAT1 activation by local Ca2+ entry.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33941685","citation_count":47,"is_preprint":false},{"pmid":"19091974","id":"PMC_19091974","title":"Stable membrane expression of postsynaptic CaV1.2 calcium channel clusters is independent of interactions with AKAP79/150 and PDZ proteins.","date":"2008","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/19091974","citation_count":46,"is_preprint":false},{"pmid":"15458848","id":"PMC_15458848","title":"Modulation of dopamine mediated phosphorylation of AMPA receptors by PSD-95 and AKAP79/150.","date":"2004","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15458848","citation_count":46,"is_preprint":false},{"pmid":"21273417","id":"PMC_21273417","title":"AKAP79/150 impacts intrinsic excitability of hippocampal neurons through phospho-regulation of A-type K+ channel trafficking.","date":"2011","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21273417","citation_count":46,"is_preprint":false},{"pmid":"18305116","id":"PMC_18305116","title":"AKAP79 selectively enhances protein kinase C regulation of GluR1 at a Ca2+-calmodulin-dependent protein kinase II/protein kinase C site.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18305116","citation_count":46,"is_preprint":false},{"pmid":"29196604","id":"PMC_29196604","title":"CaMKII regulates the depalmitoylation and synaptic removal of the scaffold protein AKAP79/150 to mediate structural long-term depression.","date":"2017","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29196604","citation_count":45,"is_preprint":false},{"pmid":"19858198","id":"PMC_19858198","title":"Ca2+/calmodulin-dependent protein kinase II binds to and phosphorylates a specific SAP97 splice variant to disrupt association with AKAP79/150 and modulate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor (AMPAR) activity.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19858198","citation_count":45,"is_preprint":false},{"pmid":"24121510","id":"PMC_24121510","title":"Role of AKAP79/150 protein in β1-adrenergic receptor trafficking and signaling in mammalian cells.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24121510","citation_count":44,"is_preprint":false},{"pmid":"23699529","id":"PMC_23699529","title":"Mapping the binding site of TRPV1 on AKAP79: implications for inflammatory hyperalgesia.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23699529","citation_count":40,"is_preprint":false},{"pmid":"16442664","id":"PMC_16442664","title":"G-Protein-coupled receptor-associated A-kinase anchoring proteins: AKAP79 and AKAP250 (gravin).","date":"2006","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16442664","citation_count":37,"is_preprint":false},{"pmid":"33082339","id":"PMC_33082339","title":"AKAP5 complex facilitates purinergic modulation of vascular L-type Ca2+ channel CaV1.2.","date":"2020","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33082339","citation_count":37,"is_preprint":false},{"pmid":"32601188","id":"PMC_32601188","title":"STIM2 targets Orai1/STIM1 to the AKAP79 signaling complex and confers coupling of Ca2+ entry with NFAT1 activation.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32601188","citation_count":36,"is_preprint":false},{"pmid":"16246112","id":"PMC_16246112","title":"Beta-arrestin-recruited phosphodiesterase-4 desensitizes the AKAP79/PKA-mediated switching of beta2-adrenoceptor signalling to activation of ERK.","date":"2005","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/16246112","citation_count":35,"is_preprint":false},{"pmid":"19055733","id":"PMC_19055733","title":"G-protein-coupled receptor-associated A-kinase anchoring proteins AKAP5 and AKAP12: differential signaling to MAPK and GPCR recycling.","date":"2008","source":"Journal of molecular signaling","url":"https://pubmed.ncbi.nlm.nih.gov/19055733","citation_count":33,"is_preprint":false},{"pmid":"12938160","id":"PMC_12938160","title":"Identification of an IQGAP1/AKAP79 complex in beta-cells.","date":"2003","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12938160","citation_count":32,"is_preprint":false},{"pmid":"10762347","id":"PMC_10762347","title":"Localization of the A kinase anchoring protein AKAP79 in the human hippocampus.","date":"2000","source":"The European journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/10762347","citation_count":31,"is_preprint":false},{"pmid":"25225170","id":"PMC_25225170","title":"Carvedilol reverses cardiac insufficiency in AKAP5 knockout mice by normalizing the activities of calcineurin and CaMKII.","date":"2014","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/25225170","citation_count":30,"is_preprint":false},{"pmid":"31091162","id":"PMC_31091162","title":"AKAP79/150 recruits the transcription factor NFAT to regulate signaling to the nucleus by neuronal L-type Ca2+ channels.","date":"2019","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/31091162","citation_count":30,"is_preprint":false},{"pmid":"22976297","id":"PMC_22976297","title":"A key phosphorylation site in AC8 mediates regulation of Ca(2+)-dependent cAMP dynamics by an AC8-AKAP79-PKA signalling complex.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22976297","citation_count":29,"is_preprint":false},{"pmid":"23889134","id":"PMC_23889134","title":"AKAP79, PKC, PKA and PDE4 participate in a Gq-linked muscarinic receptor and adenylate cyclase 2 cAMP signalling complex.","date":"2013","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/23889134","citation_count":27,"is_preprint":false},{"pmid":"21156788","id":"PMC_21156788","title":"Ca2+/calmodulin-dependent protein kinase II inhibitors disrupt AKAP79-dependent PKC signaling to GluA1 AMPA receptors.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21156788","citation_count":24,"is_preprint":false},{"pmid":"28967377","id":"PMC_28967377","title":"Intrinsic disorder within AKAP79 fine-tunes anchored phosphatase activity toward substrates and drug sensitivity.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28967377","citation_count":24,"is_preprint":false},{"pmid":"25504574","id":"PMC_25504574","title":"Anchoring protein AKAP79-mediated PKA phosphorylation of STIM1 determines selective activation of the ARC channel, a store-independent Orai channel.","date":"2015","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25504574","citation_count":24,"is_preprint":false},{"pmid":"22232585","id":"PMC_22232585","title":"A Potential Role for a Genetic Variation of AKAP5 in Human Aggression and Anger Control.","date":"2011","source":"Frontiers in human neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22232585","citation_count":22,"is_preprint":false},{"pmid":"18950703","id":"PMC_18950703","title":"G-protein-coupled receptor-associated A-kinase anchoring proteins AKAP5 and AKAP12: differential trafficking and distribution.","date":"2008","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/18950703","citation_count":19,"is_preprint":false},{"pmid":"21561082","id":"PMC_21561082","title":"Identification of AKAP79 as a protein phosphatase 1 catalytic binding protein.","date":"2011","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21561082","citation_count":18,"is_preprint":false},{"pmid":"15914039","id":"PMC_15914039","title":"Differential expression of protein kinase A, AKAP79, and PP2B in pregnant human myometrial membranes prior to and during labor.","date":"2005","source":"Journal of the Society for Gynecologic Investigation","url":"https://pubmed.ncbi.nlm.nih.gov/15914039","citation_count":18,"is_preprint":false},{"pmid":"34612814","id":"PMC_34612814","title":"AKAP79 enables calcineurin to directly suppress protein kinase A activity.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34612814","citation_count":16,"is_preprint":false},{"pmid":"26170881","id":"PMC_26170881","title":"Curcumin Protects Neurons from Glutamate-Induced Excitotoxicity by Membrane Anchored AKAP79-PKA Interaction Network.","date":"2015","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/26170881","citation_count":15,"is_preprint":false},{"pmid":"34458850","id":"PMC_34458850","title":"AKAP79 Orchestrates a Cyclic AMP Signalosome Adjacent to Orai1 Ca2+ Channels.","date":"2021","source":"Function (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34458850","citation_count":15,"is_preprint":false},{"pmid":"21831305","id":"PMC_21831305","title":"AKAP12 and AKAP5 form higher-order hetero-oligomers.","date":"2011","source":"Journal of molecular signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21831305","citation_count":14,"is_preprint":false},{"pmid":"30737285","id":"PMC_30737285","title":"Preferential generation of Ca2+-permeable AMPA receptors by AKAP79-anchored protein kinase C proceeds via GluA1 subunit phosphorylation at Ser-831.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30737285","citation_count":14,"is_preprint":false},{"pmid":"22693956","id":"PMC_22693956","title":"AKAP79/150 interacts with the neuronal calcium-binding protein caldendrin.","date":"2012","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22693956","citation_count":14,"is_preprint":false},{"pmid":"22677788","id":"PMC_22677788","title":"AKAP79 modulation of L-type channels involves disruption of intramolecular interactions in the CaV1.2 subunit.","date":"2012","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/22677788","citation_count":14,"is_preprint":false},{"pmid":"25653013","id":"PMC_25653013","title":"Mechanisms and dynamics of AKAP79/150-orchestrated multi-protein signalling complexes in brain and peripheral nerve.","date":"2015","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25653013","citation_count":13,"is_preprint":false},{"pmid":"33617875","id":"PMC_33617875","title":"AKAP79/150 coordinates leptin-induced PKA signaling to regulate KATP channel trafficking in pancreatic β-cells.","date":"2021","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33617875","citation_count":13,"is_preprint":false},{"pmid":"29976855","id":"PMC_29976855","title":"Targeting FRET-Based Reporters for cAMP and PKA Activity Using AKAP79.","date":"2018","source":"Sensors (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/29976855","citation_count":12,"is_preprint":false},{"pmid":"21554706","id":"PMC_21554706","title":"AKAP5 and AKAP12 Form Homo-oligomers.","date":"2011","source":"Journal of molecular signaling","url":"https://pubmed.ncbi.nlm.nih.gov/21554706","citation_count":12,"is_preprint":false},{"pmid":"23462372","id":"PMC_23462372","title":"Increased density of AKAP5-expressing neurons in the anterior cingulate cortex of subjects with bipolar disorder.","date":"2013","source":"Journal of psychiatric research","url":"https://pubmed.ncbi.nlm.nih.gov/23462372","citation_count":11,"is_preprint":false},{"pmid":"20164376","id":"PMC_20164376","title":"The contribution of AKAP5 in amylase secretion from mouse parotid acini.","date":"2010","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20164376","citation_count":9,"is_preprint":false},{"pmid":"36317924","id":"PMC_36317924","title":"Nuanced Interactions between AKAP79 and STIM1 with Orai1 Ca2+ Channels at Endoplasmic Reticulum-Plasma Membrane Junctions Sustain NFAT Activation.","date":"2022","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/36317924","citation_count":8,"is_preprint":false},{"pmid":"22996592","id":"PMC_22996592","title":"Kinetic and mechanistic differences in the interactions between caldendrin and calmodulin with AKAP79 suggest different roles in synaptic function.","date":"2012","source":"Journal of molecular recognition : JMR","url":"https://pubmed.ncbi.nlm.nih.gov/22996592","citation_count":8,"is_preprint":false},{"pmid":"14519485","id":"PMC_14519485","title":"Expression and intracellular localization of protein phosphatases 2A and 2B, protein kinase a, A-Kinase anchoring protein (AKAP79), and binding of the regulatory (RII) subunit of protein kinase a to AKAP79 in human myometrium.","date":"2003","source":"Journal of the Society for Gynecologic Investigation","url":"https://pubmed.ncbi.nlm.nih.gov/14519485","citation_count":7,"is_preprint":false},{"pmid":"26713362","id":"PMC_26713362","title":"Modified sympathetic nerve regulation in AKAP5-null mice.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26713362","citation_count":5,"is_preprint":false},{"pmid":"24926793","id":"PMC_24926793","title":"AKAP5 keeps L-type channels and NFAT on their toes.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24926793","citation_count":5,"is_preprint":false},{"pmid":"11275698","id":"PMC_11275698","title":"Development-related expression of AKAP79 in the striatal compartments of the human brain.","date":"2001","source":"Cells, tissues, organs","url":"https://pubmed.ncbi.nlm.nih.gov/11275698","citation_count":5,"is_preprint":false},{"pmid":"25789584","id":"PMC_25789584","title":"AKAP5 signaling complexes: focal points and functional properties.","date":"2015","source":"Neuro endocrinology letters","url":"https://pubmed.ncbi.nlm.nih.gov/25789584","citation_count":4,"is_preprint":false},{"pmid":"22583680","id":"PMC_22583680","title":"\"Shaping\" of cell signaling via AKAP-tethered PDE4D: Probing with AKAR2-AKAP5 biosensor.","date":"2012","source":"Journal of molecular signaling","url":"https://pubmed.ncbi.nlm.nih.gov/22583680","citation_count":4,"is_preprint":false},{"pmid":"16460836","id":"PMC_16460836","title":"Contextual utilization of enzymes in discrete AKAP79/150 signalling complexes.","date":"2006","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16460836","citation_count":4,"is_preprint":false},{"pmid":"31310785","id":"PMC_31310785","title":"Maturation of thalamocortical synapses in the somatosensory cortex depends on neocortical AKAP5 expression.","date":"2019","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/31310785","citation_count":3,"is_preprint":false},{"pmid":"32173522","id":"PMC_32173522","title":"AKAP5 anchors PKA to enhance regulation of the HERG channel.","date":"2020","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32173522","citation_count":3,"is_preprint":false},{"pmid":"15003529","id":"PMC_15003529","title":"AKAP79 increases the functional expression of skeletal muscle Ca2+ channels in Xenopus oocytes.","date":"2004","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15003529","citation_count":3,"is_preprint":false},{"pmid":"38798824","id":"PMC_38798824","title":"Akap5 links synaptic dysfunction to neuroinflammatory signaling in a mouse model of infantile neuronal ceroid lipofuscinosis.","date":"2024","source":"Frontiers in synaptic neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38798824","citation_count":3,"is_preprint":false},{"pmid":"36238650","id":"PMC_36238650","title":"Metoprolol Mitigates Ischemic Heart Remodeling and Fibrosis by Increasing the Expression of AKAP5 in Ischemic Heart.","date":"2022","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/36238650","citation_count":2,"is_preprint":false},{"pmid":"39864527","id":"PMC_39864527","title":"Unveiling the significance of AKAP79/150 in the nervous system disorders: An emerging opportunity for future therapies?","date":"2025","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/39864527","citation_count":1,"is_preprint":false},{"pmid":"37810553","id":"PMC_37810553","title":"Retracted: Metoprolol Mitigates Ischemic Heart Remodeling and Fibrosis by Increasing the Expression of AKAP5 in Ischemic Heart.","date":"2023","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/37810553","citation_count":0,"is_preprint":false},{"pmid":"41640285","id":"PMC_41640285","title":"Maternal exercise improves vascular function in hypertensive offspring via A-kinase anchoring protein 150 gene (Akap5) epigenetic modifications.","date":"2026","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41640285","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.10.05.616758","title":"Transcriptomic Insights into Hypothalamic Aging During Menopause: A Comparative Analysis of Human and Mouse Models","date":"2024-10-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.05.616758","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.27.616460","title":"Targeting ADORA-PDE10 cAMP Microdomain: A Novel Therapeutic Approach for Pulmonary Hypertension","date":"2024-10-27","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.27.616460","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46331,"output_tokens":11475,"usd":0.155559},"stage2":{"model":"claude-opus-4-6","input_tokens":15842,"output_tokens":5571,"usd":0.327728},"total_usd":0.483287,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1996,\n      \"finding\": \"AKAP79 functions as a scaffold protein that simultaneously binds PKA, calcineurin (PP2B), and PKC at distinct sites, coordinating three signaling enzymes at the postsynaptic membrane.\",\n      \"method\": \"Deletion analysis, binding studies, co-immunoprecipitation, immunofluorescence in neurons\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — foundational study with multiple orthogonal methods, replicated extensively by subsequent labs\",\n      \"pmids\": [\"8599116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"AKAP75 (bovine ortholog of AKAP5) contains two noncontiguous N-terminal domains (residues 27–48 and 77–91) that mediate intracellular membrane targeting, and a separate C-terminal RII-binding (tethering) domain mapped to residues 392–413 via scanning mutagenesis, where hydrophobic residues are essential for high-affinity PKA-RII binding.\",\n      \"method\": \"Deletion mutagenesis, scanning mutagenesis, subcellular fractionation, RII overlay assay in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with defined domain mapping, foundational study\",\n      \"pmids\": [\"8509414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Ca²⁺/calmodulin binds AKAP79 at the same N-terminal region (residues 31–52) that binds PKC, competing with PKC for binding and releasing the inhibited kinase from the anchoring protein; calmodulin binding also reverses AKAP79-mediated inhibition of PKCβII.\",\n      \"method\": \"Calmodulin binding assays, co-immunoprecipitation from postsynaptic density preparations, immunofluorescence in hippocampal neurons, PKC activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal biochemical methods, functional readout\",\n      \"pmids\": [\"9202019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"AKAP79 membrane targeting is mediated by three basic/hydrophobic N-terminal regions (A: residues 31–52; B: 76–101; C: 116–145) that bind acidic phospholipids including PIP2; this binding is disrupted by phosphorylation and Ca²⁺/calmodulin, providing a regulatory mechanism for membrane release.\",\n      \"method\": \"GFP-tagging and in situ fluorescence targeting assays in HEK293 cells and cortical neurons, lipid vesicle binding assays, subcellular fractionation after PKA/PKC activation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including mutagenesis, lipid binding, and cell fractionation\",\n      \"pmids\": [\"9545238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"AKAP79 binds calcineurin A (CnA) at residues 30–98 and 311–336 of CnA, with the AKAP79 binding site on residues 108–280; this interaction does not require the calcineurin B subunit, occurs at a site distinct from immunophilin binding, and AKAP79 inhibits NFAT dephosphorylation and activation in intact cells.\",\n      \"method\": \"Co-immunoprecipitation, deletion mapping, NFAT reporter assay in transfected cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal mapping with functional validation via NFAT reporter\",\n      \"pmids\": [\"9765270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"AKAP79 binds PKC at the catalytic core through the N-terminal region (residues 31–52) in a lipid- and activation-independent manner, inhibiting PKC activity by displacing the pseudosubstrate domain; residues R39 and R40 in the AKAP79(31–52) peptide are essential for PKC inhibition. AKAP79 associates with conventional, novel, and atypical PKC isoforms.\",\n      \"method\": \"In vitro binding and kinase activity assays, limited proteolysis, site-directed mutagenesis, co-immunoprecipitation, immunofluorescence in hippocampal neurons\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro mechanistic assays plus mutagenesis with multiple PKC isoforms\",\n      \"pmids\": [\"10510312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"AKAP79 regulates GRK2-mediated phosphorylation of the β2-adrenergic receptor by facilitating PKA phosphorylation of GRK2 at Ser685, which increases Gβγ binding to GRK2 and promotes its membrane translocation and receptor phosphorylation; disruption of this pathway reduces receptor internalization.\",\n      \"method\": \"Overexpression/dominant-negative approaches, mutagenesis (GRK2 S685A), co-immunoprecipitation, receptor internalization assays in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — site-directed mutagenesis with defined phosphorylation site and functional cellular readout\",\n      \"pmids\": [\"11278469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"AKAP79 directly associates with the inwardly rectifying potassium channel Kir2.1 via both the intracellular N- and C-terminal domains of the channel, and this association enhances Kir2.1 responsiveness to elevated intracellular cAMP.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, electrophysiology in intact cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP and GST pulldown with functional electrophysiology, single study\",\n      \"pmids\": [\"11287423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The PP2B/calcineurin-anchoring site on AKAP79 maps to residues 315–360, which are necessary and sufficient for PP2B anchoring in cells, directly bind the PP2B A subunit, and inhibit phosphatase activity; peptides spanning this region antagonize PP2B anchoring and attenuate PP2B-dependent down-regulation of GluR1 currents.\",\n      \"method\": \"Deletion/truncation mutagenesis, cell targeting assays, in vitro phosphatase activity assays, peptide competition, electrophysiology in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro phosphatase assay plus mutagenesis plus electrophysiological functional readout\",\n      \"pmids\": [\"12354762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"AKAP79 directly regulates cell surface expression (trafficking) of L-type CaV1.2 calcium channels independently of PKA, through interaction involving a short polyproline sequence in the channel II–III cytoplasmic loop.\",\n      \"method\": \"Extracellular epitope tagging, immunoassays, whole-cell and single-channel electrophysiology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct channel expression assay with electrophysiology, mutagenesis of binding sequence\",\n      \"pmids\": [\"12114507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"AKAP79 is linked to GluR1 AMPA receptors via SAP97, promoting basal PKA-dependent phosphorylation of GluR1 Ser845, and the AKAP79–PP2B complex confers Ca²⁺-dependent downregulation of GluR1 currents mimicking LTD; this requires the PDZ interaction between GluR1 and SAP97.\",\n      \"method\": \"Co-immunoprecipitation, electrophysiology in HEK293 cells and hippocampal neurons, mutagenesis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, defined molecular mechanism with functional readout\",\n      \"pmids\": [\"11943807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"AKAP79 assembles a ternary kinase-scaffold-phosphatase complex at the plasma membrane, where PKA-RII and calcineurin bind simultaneously to AKAP79 within ~50 Å of each other, as demonstrated by FRET in living cells; AKAP79 also regulates membrane localization of SAP97.\",\n      \"method\": \"FRET microscopy (donor-dequenching and sensitized emission), immunofluorescence in living cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct FRET evidence of ternary complex in living cells, multiple FRET configurations\",\n      \"pmids\": [\"12507994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"AKAP79 interacts with IQGAP1 through the carboxyl-terminal domain of IQGAP1, forming a complex that links PKA to the IQGAP1 scaffold in β-cells.\",\n      \"method\": \"cAMP affinity chromatography co-purification, co-immunoprecipitation, direct interaction assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single pulldown/co-IP study without functional follow-up\",\n      \"pmids\": [\"12938160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"AKAP79 (constitutively associated with β2-AR) provides the PKA that mediates β2-AR phosphorylation enabling switching of β2-AR signaling from Gs to Gi/ERK activation; PDE4D5 recruited by β-arrestin desensitizes this PKA-mediated switch.\",\n      \"method\": \"siRNA knockdown of specific AKAPs and PDE4 isoforms, co-immunoprecipitation, PKA activity assays, ERK phosphorylation assays in HEK293B2 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — isoform-selective siRNA with multiple functional readouts, identifies specific AKAP and PDE isoforms\",\n      \"pmids\": [\"16030021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"AKAP79 forms a ternary complex with β1-adrenergic receptor and PKA at the receptor C-terminus, and AKAP79-anchored PKA phosphorylates β1-AR at Ser312 (third intracellular loop) to dictate recycling and resensitization itineraries of the internalized receptor.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, FRET microscopy, receptor recycling assays in HEK293 and SK-N-MC cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including FRET and functional siRNA rescue\",\n      \"pmids\": [\"16940053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"AKAP79 forms a receptosome with SAP97 at the type I PDZ motif (ESKV) of the β1-AR C-terminus; this scaffold targets PKA to phosphorylate β1-AR at Ser312, and the PDZ/scaffold complex is required for efficient receptor recycling.\",\n      \"method\": \"Co-immunoprecipitation, mutagenesis of PDZ motif, receptor recycling assays, PKA phosphorylation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — defined molecular interactions with functional receptor trafficking readout\",\n      \"pmids\": [\"17170109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"AKAP79/150 interacts directly with the CaV1.2 pore-forming subunit and co-targets PKA and calcineurin, conferring bidirectional regulation of L-type current amplitude; anchored calcineurin dominantly suppresses PKA enhancement. Additionally, AKAP79/150 is required for NFATc4 activation via local Ca²⁺ influx through L-type channels.\",\n      \"method\": \"Co-immunoprecipitation, electrophysiology in HEK293 and hippocampal neurons, NFAT reporter assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct protein interaction with bidirectional functional electrophysiology and NFAT transcription readout\",\n      \"pmids\": [\"17640527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"AKAP79/150 forms a signaling complex with TRPV1 through binding to a critical region in the TRPV1 C-terminus, and this complex scaffolds PKA, PKC, and calcineurin to mediate sensitization of TRPV1 by inflammatory mediators (bradykinin, PGE2); disruption of AKAP79/150 binding abrogates heat hyperalgesia.\",\n      \"method\": \"Co-immunoprecipitation, deletion mapping of TRPV1 C-terminal binding region, electrophysiology, in vivo hyperalgesia assay\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding site identification plus in vivo functional readout\",\n      \"pmids\": [\"18701070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"AKAP79 selectively enhances PKC-mediated phosphorylation of GluR1 at Ser831 by localizing PKC near the receptor via SAP97, shifting the dose-dependence for PKC modulation ~20-fold and making low PKC concentrations as effective as much higher CaMKII concentrations.\",\n      \"method\": \"Biochemical phosphorylation assays, electrophysiology in HEK293 cells, AKAP79-SAP97-GluR1 complex characterization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro phosphorylation assays combined with electrophysiology, quantitative dose-response analysis\",\n      \"pmids\": [\"18305116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AKAP5 organizes a caveolin-3-associated signaling module in cardiomyocytes that clusters adenylyl cyclase 5/6, PKA, calcineurin, and a specific subpopulation of CaV1.2 L-type channels; this complex is essential for β-adrenergic stimulation of calcium transients and PKA phosphorylation of ryanodine receptors and phospholamban. In AKAP5 KO, AC5/6 is displaced from caveolin-3 T-tubule complexes.\",\n      \"method\": \"AKAP5 knockout mice, calcium imaging, electrophysiology, co-immunoprecipitation, phosphorylation assays\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with multiple orthogonal functional readouts\",\n      \"pmids\": [\"20671242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AKAP79 interacts with multiple adenylyl cyclase isoforms (AC5, AC6, AC9) via their N-terminal regions, with a reciprocal binding surface on AKAP79 at residues 77–108; loss of AKAP150 decreases AMPA receptor-associated AC activity in brain.\",\n      \"method\": \"Co-immunoprecipitation, FRET (intensity- and lifetime-based) in living cells, peptide competition, brain extracts from AKAP150 KO mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — FRET mapping plus genetic mouse model validation\",\n      \"pmids\": [\"20231277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AKAP79 anchors a muscarinic-receptor-activated pool of PKC that phosphorylates the KCNQ2 subunit of M-channels to enhance neuronal excitability; AKAP79 also protects anchored PKC from certain ATP-competitive inhibitors, modifying the cellular pharmacology of PKC.\",\n      \"method\": \"Dual fluorescent imaging/patch-clamp, FRET-based kinase activity reporter (CKAR), electrophysiology, pharmacological inhibitor profiling\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — simultaneous imaging and electrophysiology in living cells, novel pharmacological phenotype\",\n      \"pmids\": [\"20188672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AKAP79/150 directly associates with Ca²⁺-stimulable adenylyl cyclase 8 (AC8) and limits the sensitivity of AC8 to intracellular Ca²⁺, as shown in HEK293 cells, pancreatic insulin-secreting cells, and hippocampal neurons.\",\n      \"method\": \"Co-immunoprecipitation, live-cell Ca²⁺ and cAMP imaging in multiple cell types\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — replicated in three independent cell types with live-cell imaging\",\n      \"pmids\": [\"20410303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Ca²⁺/calmodulin disrupts AKAP79/150 interaction with KCNQ2–5 (but not KCNQ1) M-type channels at the plasma membrane, preventing AKAP79-mediated sensitization of these channels to muscarinic inhibition; AKAP79 associates with M1 and AT1 receptors and KCNQ2/3 channels as shown by TIRF/FRET.\",\n      \"method\": \"TIRF/FRET microscopy, perforated patch-clamp electrophysiology, KCNQ subunit mutagenesis (T553A), dominant-negative calmodulin\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — FRET plus electrophysiology with mutagenesis, subtype specificity established\",\n      \"pmids\": [\"20147557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AKAP5 deletion in hippocampal and striatal neurons causes delocalization of PKA to dendritic shafts with increased binding to MAP2; the PKA-binding domain of AKAP5 is specifically required to maintain PKA near postsynaptic sites for synaptic plasticity and operant learning.\",\n      \"method\": \"AKAP5 KO and D36 (PKA-binding domain deletion) knock-in mice, electrophysiology, behavioral assays, immunofluorescence\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic models with defined domain deletion, electrophysiology, and behavioral phenotyping\",\n      \"pmids\": [\"20428246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"AKAP79 dimerizes (stabilized by K328–K328 and K333–K333 cross-links) and, upon addition of Ca²⁺/CaM, assembles a 466-kDa complex comprising dimeric AKAP79 coordinating two RII homodimers, four PP2B heterodimers, and two CaM molecules; Ca²⁺/CaM binding generates a second interface for PP2B, activating anchored phosphatase.\",\n      \"method\": \"Native mass spectrometry, chemical cross-linking, quantitative biochemical reconstitution\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — native MS with reconstitution defines stoichiometry and activation mechanism\",\n      \"pmids\": [\"21464287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Palmitoylation of AKAP79 at two N-terminal cysteines is required for targeting to lipid rafts in HEK293 cells; loss of palmitoylation excludes AKAP79 from rafts, alters membrane diffusion, and abolishes AKAP79-dependent regulation of SOCE-stimulated AC8 activity and PKA-dependent phosphorylation of raft proteins.\",\n      \"method\": \"Mutagenesis of palmitoylation cysteines, pharmacological depalmitoylation, sucrose density fractionation (lipid raft isolation), FRAP, AC activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mutagenesis plus multiple biochemical and functional assays\",\n      \"pmids\": [\"21771783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"AKAP79/150 anchors PKA to regulate Kv4.2 (A-type K⁺ channel) surface expression in hippocampal neurons; the Kv4.2 C-terminal domain interacts with an internal region of AKAP79/150 overlapping its MAGUK-binding domain, and disrupting PKA anchoring decreases neuronal excitability while blocking calcineurin dephosphorylation increases excitability.\",\n      \"method\": \"Co-immunoprecipitation, surface biotinylation assay, patch-clamp electrophysiology, PKA anchoring disruption (Ht31 peptide)\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction mapping with bidirectional functional electrophysiology readout\",\n      \"pmids\": [\"21273417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"AKAP79 is a novel PP1 regulatory subunit: it directly binds PP1 via a consensus FxxR/KxR/K motif in its first 44 amino acids (enhancing PP1 activity) and a second inhibitory domain at residues 150–250; AKAP79 inhibition of PP1 is substrate-dependent.\",\n      \"method\": \"Co-immunoprecipitation from rat brain, pulldown with purified proteins, PP1 activity assays, surface plasmon resonance, deletion mutagenesis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro assay with purified proteins plus SPR and mutagenesis\",\n      \"pmids\": [\"21561082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The IAIIIT anchoring motif in human AKAP79 (residues 337–343) binds the same surface of calcineurin as the PxIxIT recognition peptide of NFAT; higher-affinity AKAP–calcineurin interaction impairs NFAT activation by slowing calcineurin release and sequestering it at decoy sites, revealing an optimal affinity window for NFAT signaling.\",\n      \"method\": \"Structural analysis, mutagenesis of anchoring sequence, calcineurin binding assays, NFAT reporter assays in hippocampal neurons\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — structural plus functional mutagenesis with neuronal NFAT activation assay\",\n      \"pmids\": [\"22343722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"AKAP79 recruits and scaffolds an AC8–AKAP79–PKA signaling complex; PKA phosphorylates AC8 at Ser112 to provide feedback inhibition of Ca²⁺-stimulated cAMP synthesis, reducing the on-rate of cAMP production during Ca²⁺ oscillations.\",\n      \"method\": \"Site-directed mutagenesis (Ser112), live-cell cAMP imaging during Ca²⁺ oscillations, co-immunoprecipitation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis of phosphorylation site with live-cell functional imaging\",\n      \"pmids\": [\"22976297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CaMKIIα phosphorylates a specific SAP97 splice variant (containing I3 and I5 inserts) to disrupt its interaction with AKAP79/150, thereby disengaging AKAP79/150 from regulating GluR1 AMPA receptors.\",\n      \"method\": \"Co-immunoprecipitation, in vitro and cell-based phosphorylation assays, GST pulldowns of splice variants, electrophysiology in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — splice-variant specific mechanism with in vitro phosphorylation and electrophysiology\",\n      \"pmids\": [\"19858198\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"AKAP79/150 interacts with the neuronal calcium-binding protein caldendrin; caldendrin and calmodulin compete for a partially overlapping binding site on AKAP79 (B-domain), with different Ca²⁺ dependencies—calmodulin binds only with Ca²⁺ via a simple 1-step mechanism, while caldendrin uses an induced-fit mechanism and can bind independent of Ca²⁺.\",\n      \"method\": \"GST pulldown, surface plasmon resonance biosensor analysis, kinetic interaction modeling\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — SPR with kinetic modeling defines mechanism and competition at molecular level\",\n      \"pmids\": [\"22693956\", \"22996592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"AKAP79 modulates CaV1.2 L-type channel membrane targeting through relief of an autoinhibitory interaction between the channel's distal C-terminus and the II–III linker; the distal C-terminus of CaV1.2 directly interacts with AKAP79.\",\n      \"method\": \"Mutagenesis of polyproline domains, co-immunoprecipitation, channel membrane expression assay\",\n      \"journal\": \"Channels\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — mechanistic model supported by mutagenesis and co-IP, single study\",\n      \"pmids\": [\"22677788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"AKAP79/150-mediated calcineurin–NFAT signaling drives activity-dependent transcriptional upregulation of KCNQ2/3 M-channels in hippocampal neurons; this requires Ca²⁺ influx through L-type channels and is absent in AKAP150⁻/⁻ mice after seizures.\",\n      \"method\": \"AKAP150 KO mice, in vivo seizure induction, KCNQ2/3 mRNA quantification, NFAT reporter assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with in vivo seizure model plus NFAT reporter\",\n      \"pmids\": [\"23259949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The AKAP79–TRPV1 interaction is mediated by a region on AKAP79 between amino acids 326–336; a peptide from this domain inhibits TRPV1 sensitization in vitro, and a cell-penetrant TAT-linked version inhibits inflammatory hyperalgesia in mice without affecting basal pain thresholds.\",\n      \"method\": \"FRET, co-immunoprecipitation, TRPV1 membrane trafficking assay, in vivo hyperalgesia assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct mapping of binding site with in vivo functional validation\",\n      \"pmids\": [\"23699529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AKAP5 anchoring of adenylyl cyclase (in addition to PKA) is required for β-adrenergic stimulation of GluA1 Ser845 phosphorylation and for LTP induced by 5-Hz θ-rhythm stimulation; AKAP5 KO (lacking both AC and PKA anchoring) produces much greater impairment than D36 (PKA-binding deletion only).\",\n      \"method\": \"AKAP5 KO and D36 knock-in mice, phosphorylation assays, hippocampal slice electrophysiology (LTP), β-adrenergic stimulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic dissection of AC vs PKA anchoring with LTP readout\",\n      \"pmids\": [\"23649627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AKAP5-anchored PKA controls GluA1 S845 phosphorylation and AMPAR surface trafficking during homeostatic scaling; PKA is lost from synapses during scaling down and enriched during scaling up; knockdown of AKAP5 blocks scaling up.\",\n      \"method\": \"siRNA knockdown of AKAP5, FRET-based PKA activity reporters, GluA1 S845 phosphorylation assays, surface AMPAR assays, GluA1 S845 knockin mice\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, genetic knockin validation\",\n      \"pmids\": [\"25451194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The recycling endosome-resident palmitoyl acyltransferase DHHC2 interacts with and palmitoylates AKAP79/150, targeting it to recycling endosomes in dendrites; DHHC2 knockdown disrupts recycling endosome exocytosis, spine enlargement, AKAP recruitment to spines, and LTP-induced AMPAR synaptic potentiation.\",\n      \"method\": \"RNAi knockdown, palmitoylation assay, dendritic exocytosis assay, spine morphology, AMPAR synaptic current recordings, rescue with lipidated AKAP mutant\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — identifies the palmitoyl transferase (DHHC2) and validates with rescue experiment\",\n      \"pmids\": [\"25589740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AKAP79-anchored PKA phosphorylates STIM1 at T389 in the plasma membrane pool; this phosphorylation is specifically required for activation of store-independent ARC channels (but actually inhibits STIM1-dependent CRAC channel activation), demonstrating selective regulation of two co-existing Orai channel types.\",\n      \"method\": \"Site-directed mutagenesis (T389A), co-immunoprecipitation, patch-clamp electrophysiology, knockdown of AKAP79\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — phosphorylation site mutagenesis with functional electrophysiological readout\",\n      \"pmids\": [\"25504574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Intrinsic disorder in AKAP79 produces an ensemble of AKAP79–PP2B configurations; a short linear motif (residues 337–343) is the sole PP2B-anchoring determinant; Ca²⁺/CaM engagement of additional surfaces (including Leu-Lys-Ile-Pro, residues 125–128) condenses configurational variants and fine-tunes phosphatase activity and cyclosporin sensitivity.\",\n      \"method\": \"Negative-stain electron microscopy, chemical cross-linking, live-cell fluorescent activity sensors (NFAT translocation), site-directed mutagenesis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural EM combined with mutagenesis and live-cell functional reporters\",\n      \"pmids\": [\"28967377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LTD-induced synaptic removal of AKAP79/150 requires CaMKII activity and depalmitoylation of two N-terminal Cys residues; CaMKII phosphorylates AKAP79/150's N-terminal polybasic domain (inhibiting F-actin association) preferentially via autonomous (Thr286-autophosphorylated) CaMKII; Ca²⁺/CaM binding to the substrate sites protects them from phosphorylation in the presence of strong LTP stimuli, providing stimulus-selective regulation.\",\n      \"method\": \"CaMKII inhibitors and knockout, LTD induction in hippocampal neurons, palmitoylation assay, spine morphology, actin-binding assay, phospho-site mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection with multiple methods, identifies depalmitoylation as primary mechanism over direct phosphorylation\",\n      \"pmids\": [\"29196604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AKAP79 recruits the transcription factor NFAT via a C-terminal leucine-zipper (LZ) domain, forming a direct AKAP79–NFAT complex at the plasma membrane; this LZ-mediated NFAT recruitment (not the LTCC–AKAP interaction per se) is required for depolarization-induced NFAT signaling in hippocampal neurons.\",\n      \"method\": \"RNAi knockdown + replacement with LZ-deletion mutant, co-immunoprecipitation, FRET, Ca²⁺ imaging, FRAP, fluorescence correlation spectroscopy, electrophysiology\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple imaging and electrophysiological methods with defined domain mutant\",\n      \"pmids\": [\"31091162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AKAP5 organizes a nanocomplex containing P2Y11/P2Y11-like receptors, AC5, PKA, and CaV1.2 at the plasma membrane of arterial myocytes; disruption of AKAP5 blocks glucose- and P2Y11-induced cAMP synthesis, CaV1.2 potentiation, and vasoconstriction.\",\n      \"method\": \"AKAP5 KO mice, calcium imaging, proximity ligation assay, TIRF microscopy, patch-clamp, myography\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple functional vascular readouts\",\n      \"pmids\": [\"33082339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STIM2 recruits Orai1/STIM1 to ER–PM junctions and promotes assembly with AKAP79 to couple Orai1 channel function to NFAT1 activation; STIM2 polybasic domain mediates this assembly. Loss of STIM2 impairs NFAT1 activation and Orai1–AKAP79 association without significantly affecting global Ca²⁺.\",\n      \"method\": \"Co-immunoprecipitation, knockdown, STIM1ΔK mutant, NFAT1 translocation assay, Ca²⁺ imaging\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic tools with defined molecular requirements\",\n      \"pmids\": [\"32601188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The N-terminus of Orai1 (lacking in Orai2, Orai3, and short Orai1) contains an AKAP79-interaction site required for excitation-transcription coupling; NMR reveals a compact, proline-driven structure at this site; disrupting Orai1–AKAP79 interaction suppresses cytokine production without affecting other Orai1 functions.\",\n      \"method\": \"NMR structural analysis, co-immunoprecipitation, NFAT1 translocation assay, cytokine production assay, Orai isoform comparison\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — NMR structure with functional validation in intact cells\",\n      \"pmids\": [\"33941685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AKAP79 increases the rate of calcineurin dephosphorylation of type II PKA regulatory (RII) subunits by ~10-fold, enabling calcineurin to suppress PKA activity without altering cAMP levels by increasing catalytic subunit capture rate; kinetic modeling and hippocampal neuron experiments indicate this contributes to LTD.\",\n      \"method\": \"In vitro phosphatase activity assay, fluorescent PKA activity reporter, kinetic modeling, hippocampal neuron electrophysiology\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution with kinetic modeling plus neuronal functional validation\",\n      \"pmids\": [\"34612814\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AKAP79/150 coordinates leptin-induced PKA signaling at the cell membrane to regulate KATP channel trafficking in pancreatic β-cells; AKAP79/150 knockdown abolishes leptin-induced membrane PKA activity increases; disrupting PP2B anchoring to AKAP79/150 elevates basal PKA signaling and increases surface KATP channels.\",\n      \"method\": \"FRET-based PKA reporters, siRNA knockdown, KATP channel surface assay, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — FRET reporters with genetic knockdown and domain-specific disruption\",\n      \"pmids\": [\"33617875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"AKAP79/150 pre-assembled with RXFP1 (relaxin receptor), AC2, β-arrestin 2, and PDE4D3 forms a constitutively active signalosome; AC2 is functionally coupled to RXFP1 through AKAP79 binding to helix 8 of RXFP1; PKA-activated PDE4D3 (via β-arrestin 2 on Ser704 of RXFP1) provides tonic opposition to cAMP, enabling sub-picomolar relaxin signaling.\",\n      \"method\": \"Co-immunoprecipitation, cAMP biosensors in single cells, deletion mapping, mutagenesis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — single-cell biosensors with molecular mapping of complex components\",\n      \"pmids\": [\"20664520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AKAP79-anchored PKC phosphorylates GluA1 at Ser831, which is sufficient to drive appearance of Ca²⁺-permeable (GluA2-lacking) AMPARs; other AKAP79 signaling components (PKA/calcineurin) and C-terminal phosphorylation sites play a permissive/limiting role.\",\n      \"method\": \"Electrophysiology (I-V relationships), mutagenesis of GluA1 phosphorylation sites, AKAP79 deletion mutants in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — defined phosphorylation site with electrophysiological readout of receptor Ca²⁺ permeability\",\n      \"pmids\": [\"30737285\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AKAP5 (AKAP79/150) is a multivalent postsynaptic scaffold protein that simultaneously anchors PKA, calcineurin (PP2B), PKC, adenylyl cyclases (AC5/6/8), and the transcription factor NFAT at the plasma membrane via distinct binding domains; membrane targeting is mediated by N-terminal polybasic regions that bind PIP2 and are regulated by palmitoylation (via DHHC2), phosphorylation, and Ca²⁺/calmodulin, while the scaffold organizes bidirectional phosphoregulation of CaV1.2 channels, TRPV1, AMPA receptors (GluA1 Ser831/Ser845), KCNQ M-channels, Kv4.2, and adrenergic receptors, and couples local Ca²⁺ entry through Orai1 and L-type channels to calcineurin-dependent NFAT activation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"AKAP5 (AKAP79 in human, AKAP150 in rodents) is a multivalent scaffold protein that orchestrates bidirectional phospho-signaling at the plasma membrane by simultaneously anchoring PKA, calcineurin (PP2B), PKC, PP1, and adenylyl cyclases (AC5/6/8/9) through distinct, mapped binding domains, thereby coordinating the phosphorylation state of ion channels, receptors, and transcription factors in neurons, cardiomyocytes, smooth muscle, and pancreatic β-cells [PMID:8599116, PMID:21561082, PMID:20231277]. Membrane targeting depends on three N-terminal polybasic regions that bind PIP2, with dynamic regulation by palmitoylation (via DHHC2), Ca²⁺/calmodulin displacement, and CaMKII phosphorylation controlling stimulus-selective trafficking into and out of dendritic spines during LTP and LTD [PMID:9545238, PMID:25589740, PMID:29196604]. The scaffold assembles as a dimer that positions PKA-RII and calcineurin within ~50 Å, enabling calcineurin to accelerate RII dephosphorylation ~10-fold and thereby suppress PKA without changing cAMP, while PKC anchored to the same complex phosphorylates substrates such as GluA1 Ser831 and KCNQ2 to control AMPA receptor calcium permeability and M-channel excitability [PMID:12507994, PMID:34612814, PMID:20188672, PMID:30737285]. AKAP5 also recruits NFAT via a C-terminal leucine zipper and couples local Ca²⁺ entry through CaV1.2 and Orai1 to calcineurin-dependent NFAT nuclear translocation, linking channel activity to gene expression programs including activity-dependent KCNQ2/3 upregulation [PMID:31091162, PMID:33941685, PMID:23259949].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Identification of the membrane-targeting and PKA-RII-binding domains established that AKAP5 uses physically separable determinants for subcellular localization versus kinase anchoring.\",\n      \"evidence\": \"Deletion and scanning mutagenesis of bovine AKAP75 in HEK293 cells with RII overlay assay\",\n      \"pmids\": [\"8509414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid specificity of membrane-targeting domains not yet defined\", \"Structure of the RII-binding helix not resolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstration that a single scaffold simultaneously binds PKA, calcineurin, and PKC at distinct sites established the multivalent signaling-hub concept for AKAPs.\",\n      \"evidence\": \"Deletion analysis, co-immunoprecipitation, and immunofluorescence in hippocampal neurons\",\n      \"pmids\": [\"8599116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of multi-enzyme assembly unknown\", \"Functional consequences for substrates not yet tested\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Discovery that Ca²⁺/calmodulin competes with PKC for the same N-terminal AKAP79 region revealed a Ca²⁺-dependent switch controlling which enzyme occupies the scaffold.\",\n      \"evidence\": \"Calmodulin binding assays and PKC activity assays from postsynaptic density preparations\",\n      \"pmids\": [\"9202019\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo dynamics of CaM/PKC competition not measured\", \"Whether CaM displaces PKC during synaptic activity unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Mapping PIP2-dependent membrane anchoring to three polybasic N-terminal regions and showing their disruption by phosphorylation and Ca²⁺/CaM established a regulated membrane-release mechanism for the scaffold.\",\n      \"evidence\": \"GFP targeting assays, lipid vesicle binding, subcellular fractionation in HEK293 and cortical neurons\",\n      \"pmids\": [\"9545238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of palmitoylating enzyme unknown at this time\", \"Whether membrane release occurs during synaptic plasticity not shown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Elucidation that AKAP79 inhibits PKC by displacing its pseudosubstrate domain via R39/R40 contacts explained how the scaffold holds PKC in an inactive-but-releasable state.\",\n      \"evidence\": \"In vitro kinase assays, limited proteolysis, and site-directed mutagenesis with multiple PKC isoforms\",\n      \"pmids\": [\"10510312\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of pseudosubstrate displacement not resolved\", \"Release kinetics in cells unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"A series of studies established that AKAP79 connects to AMPA receptors via SAP97 to mediate PKA-dependent GluA1 Ser845 phosphorylation and calcineurin-dependent current rundown, providing a molecular mechanism for bidirectional synaptic plasticity and a direct role in LTD-like processes.\",\n      \"evidence\": \"Co-immunoprecipitation, electrophysiology in HEK293 and hippocampal neurons, FRET microscopy showing PKA-RII and calcineurin within ~50 Å on the scaffold\",\n      \"pmids\": [\"11943807\", \"12354762\", \"12507994\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this complex operates at single identified synapses in vivo not shown\", \"Relative contribution of PP2B versus PP1 in LTD unclear\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstration that AKAP79 controls CaV1.2 surface expression via the channel's II–III loop polyproline motif revealed a PKA-independent scaffolding function for channel trafficking.\",\n      \"evidence\": \"Extracellular epitope tagging, single-channel and whole-cell electrophysiology\",\n      \"pmids\": [\"12114507\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which AKAP79 relieves autoinhibition of CaV1.2 not fully resolved\", \"In vivo cardiac consequences not tested at this point\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of AKAP79 as the specific AKAP that provides PKA for β2-AR Gs-to-Gi switching, opposed by PDE4D5/β-arrestin, placed AKAP5 at the center of GPCR signaling bias.\",\n      \"evidence\": \"Isoform-selective siRNA, PKA activity assays, ERK phosphorylation in HEK293B2 cells\",\n      \"pmids\": [\"16030021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this mechanism operates in cardiomyocytes or neurons not tested\", \"Direct structural interface between AKAP79 and β2-AR not mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showing that AKAP79–SAP97 forms a receptosome with β1-AR where PKA phosphorylation at Ser312 dictates recycling defined the scaffold's role in receptor resensitization.\",\n      \"evidence\": \"siRNA, FRET, receptor recycling assays, PDZ motif mutagenesis in HEK293 and SK-N-MC cells\",\n      \"pmids\": [\"16940053\", \"17170109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether recycling pathway is conserved across all β1-AR-expressing tissues unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Co-targeting of PKA and calcineurin to CaV1.2 by AKAP79/150 was shown to produce bidirectional L-type current regulation with dominant calcineurin suppression, and to couple local Ca²⁺ entry to NFAT activation—linking channel regulation to gene expression.\",\n      \"evidence\": \"Co-immunoprecipitation, electrophysiology in HEK293 and hippocampal neurons, NFAT reporter assays\",\n      \"pmids\": [\"17640527\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NFAT isoform selectivity exists in this complex not addressed\", \"Distance constraints between channel pore and calcineurin active site unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapping the AKAP79–TRPV1 interaction to the TRPV1 C-terminus and demonstrating that the complex mediates inflammatory heat hyperalgesia in vivo extended the scaffold's role to nociception.\",\n      \"evidence\": \"Deletion mapping, electrophysiology, in vivo hyperalgesia assays\",\n      \"pmids\": [\"18701070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TRPV1–AKAP79 binding not resolved\", \"Contribution of individual enzymes (PKA vs PKC vs calcineurin) to sensitization not fully parsed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Multiple 2010 studies collectively established that AKAP5 anchors adenylyl cyclases (AC5/6/8/9) via residues 77–108, organizes them in caveolin-3 complexes in cardiomyocytes for β-adrenergic calcium transients, limits AC8 Ca²⁺ sensitivity, and anchors PKC to KCNQ2 M-channels—demonstrating the scaffold coordinates both cAMP production and ion channel modulation.\",\n      \"evidence\": \"AKAP5 KO mice, FRET in living cells, calcium imaging, electrophysiology, AC activity assays in brain extracts\",\n      \"pmids\": [\"20671242\", \"20231277\", \"20410303\", \"20188672\", \"20147557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AC isoform selectivity differs between cell types not resolved\", \"Structural basis for AC N-terminal interaction with AKAP79 unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Genetic dissection using AKAP5 KO versus D36 (PKA-binding-deleted) knock-in mice proved that PKA anchoring by AKAP5 is specifically required for postsynaptic PKA localization, synaptic plasticity, and operant learning.\",\n      \"evidence\": \"KO and domain-deletion knock-in mice, electrophysiology, immunofluorescence, behavioral assays\",\n      \"pmids\": [\"20428246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of calcineurin-anchoring versus PKA-anchoring to learning not separated in this study\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Native mass spectrometry revealed AKAP79 dimerizes and assembles a 466-kDa complex with defined stoichiometry (2 AKAP79 : 2 RII dimers : 4 PP2B heterodimers : 2 CaM), where Ca²⁺/CaM generates a second PP2B interface to activate anchored phosphatase.\",\n      \"evidence\": \"Native mass spectrometry, chemical cross-linking, quantitative reconstitution\",\n      \"pmids\": [\"21464287\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How dimerization interfaces relate to substrate access unknown\", \"Whether dimeric vs monomeric forms differ in cellular context not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of N-terminal palmitoylation sites as required for lipid-raft targeting, AC8 regulation, and raft-associated PKA signaling established lipid modification as a major determinant of scaffold compartmentalization.\",\n      \"evidence\": \"Palmitoylation-site mutagenesis, FRAP, lipid-raft fractionation, AC activity assays in HEK293 cells\",\n      \"pmids\": [\"21771783\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of palmitoyl acyltransferase not determined at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The calcineurin-anchoring motif IAIIIT (residues 337–343) was shown to occupy the same PxIxIT surface on calcineurin as NFAT, establishing an optimal-affinity window where too-tight AKAP–calcineurin binding sequesters calcineurin away from NFAT substrates.\",\n      \"evidence\": \"Structural analysis, mutagenesis of anchoring sequence, NFAT reporter assays in hippocampal neurons\",\n      \"pmids\": [\"22343722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full atomic-resolution structure of AKAP79–calcineurin complex not available\", \"Whether affinity tuning is dynamically regulated in vivo unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"AKAP79/150–calcineurin–NFAT signaling was shown to drive activity-dependent transcriptional upregulation of KCNQ2/3 after seizures, requiring L-type Ca²⁺ influx and absent in AKAP150 KO mice, establishing a gene-expression feedback loop from channel to scaffold to transcription.\",\n      \"evidence\": \"AKAP150 KO mice, in vivo seizure induction, KCNQ2/3 mRNA quantification, NFAT reporter assays\",\n      \"pmids\": [\"23259949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of NFAT target genes regulated by AKAP150 not identified\", \"Whether this loop operates in non-seizure physiological activity unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of DHHC2 as the palmitoyl acyltransferase that palmitoylates AKAP79/150 on recycling endosomes, and demonstration that this is required for LTP-induced spine delivery and AMPAR potentiation, completed the palmitoylation-dependent trafficking mechanism.\",\n      \"evidence\": \"RNAi knockdown, palmitoylation assay, exocytosis assay, spine morphology, AMPAR recordings, rescue with lipidated AKAP mutant\",\n      \"pmids\": [\"25589740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether depalmitoylation during LTD uses a specific thioesterase not identified\", \"Kinetics of palmitoylation cycling at single spines unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Negative-stain EM and mutagenesis revealed that intrinsic disorder in AKAP79 allows an ensemble of configurations with calcineurin; Ca²⁺/CaM engagement of additional motifs (including LKIP at residues 125–128) condenses the ensemble, fine-tuning phosphatase activity and drug sensitivity.\",\n      \"evidence\": \"Negative-stain EM, chemical cross-linking, NFAT translocation reporters, mutagenesis\",\n      \"pmids\": [\"28967377\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the full-length complex still lacking\", \"How ensemble condensation changes substrate selectivity in cells not measured\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CaMKII was shown to drive LTD-associated synaptic removal of AKAP79/150 by promoting depalmitoylation and phosphorylating the N-terminal polybasic domain to inhibit F-actin binding, with Ca²⁺/CaM protecting these sites during LTP-type stimuli—explaining stimulus-selective scaffold trafficking.\",\n      \"evidence\": \"CaMKII inhibitors/KO, LTD induction, palmitoylation assay, actin-binding assay, phospho-site mutagenesis in hippocampal neurons\",\n      \"pmids\": [\"29196604\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific CaMKII phospho-sites on AKAP150 not all mapped\", \"Whether CaM protection is quantitatively sufficient in all stimulus regimes unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that AKAP79 recruits NFAT via a C-terminal leucine zipper (rather than through the LTCC interaction alone) resolved how the scaffold pre-positions NFAT near local Ca²⁺ sources for excitation–transcription coupling.\",\n      \"evidence\": \"LZ-deletion mutant replacement, co-IP, FRET, Ca²⁺ imaging, FCS in hippocampal neurons\",\n      \"pmids\": [\"31091162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the LZ domain recruits other transcription factors not tested\", \"Structural basis of AKAP79 LZ–NFAT interaction not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"AKAP5 was shown to organize a P2Y11–AC5–PKA–CaV1.2 nanocomplex in arterial myocytes required for glucose-induced vasoconstriction, extending the scaffold's physiological roles to vascular tone regulation.\",\n      \"evidence\": \"AKAP5 KO mice, proximity ligation assay, TIRF, patch-clamp, myography\",\n      \"pmids\": [\"33082339\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this complex is altered in diabetes not tested\", \"Precise stoichiometry in vascular smooth muscle unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"NMR structural analysis of the Orai1 N-terminus revealed a compact proline-driven structure mediating AKAP79 binding that is unique to full-length Orai1, and disrupting this interface suppressed NFAT-dependent cytokine production without affecting other Orai1 functions—establishing a selective excitation–transcription coupling mechanism.\",\n      \"evidence\": \"NMR, co-IP, NFAT translocation, cytokine assay, Orai isoform comparison\",\n      \"pmids\": [\"33941685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether pharmacological disruption of Orai1–AKAP79 is therapeutically viable not tested\", \"Full interface structure at atomic resolution not available\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reconstitution showed AKAP79 accelerates calcineurin-mediated RII dephosphorylation ~10-fold, enabling calcineurin to suppress PKA activity without changing cAMP—establishing a cAMP-independent mechanism for PKA inhibition during LTD.\",\n      \"evidence\": \"In vitro phosphatase assay, fluorescent PKA activity reporter, kinetic modeling, hippocampal neuron electrophysiology\",\n      \"pmids\": [\"34612814\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this mechanism contributes to non-neuronal AKAP5 functions not tested\", \"Relative importance versus direct catalytic subunit inhibition not quantified in vivo\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"High-resolution structural determination of the full-length AKAP79 dimer in complex with its enzyme cohort, and understanding how the intrinsically disordered scaffold selects among multiple substrates in a stimulus-specific manner, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No atomic-resolution structure of full-length AKAP79 or its multi-enzyme complexes\", \"Mechanisms governing substrate selectivity among co-anchored enzymes in physiological settings largely inferred from reconstitution\", \"Whether AKAP5 mutations contribute to human neurological or cardiovascular disease not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 11, 25]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 8, 28, 46]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3, 11, 26, 43]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [38]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 13, 14, 16, 48]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [10, 24, 27, 34, 37]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [9, 16, 19, 43]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 29, 34, 42]}\n    ],\n    \"complexes\": [\n      \"AKAP79–PKA-RII–calcineurin ternary complex\",\n      \"AKAP79–SAP97–GluA1 complex\",\n      \"AKAP79–AC5/6/8–PKA signalosome\",\n      \"AKAP79–CaV1.2–PKA–calcineurin complex\"\n    ],\n    \"partners\": [\n      \"PRKAR2A\",\n      \"PPP3CA\",\n      \"DLG1\",\n      \"ADCY8\",\n      \"ADCY5\",\n      \"CACNA1C\",\n      \"TRPV1\",\n      \"ORAI1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}