{"gene":"CAMK2A","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1998,"finding":"CaMKIIβ binds F-actin in dendritic spines and cell cortex while CaMKIIα is largely cytosolic; when co-expressed, the two isoforms form large heterooligomers, and a small fraction of CaMKIIβ is sufficient to dock the predominant CaMKIIα to the actin cytoskeleton, establishing CaMKIIβ as a targeting module for CaMKIIα localization.","method":"GFP-tagged CaMKII isoform live imaging, co-expression in neurons, F-actin co-localization assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct live-cell imaging with GFP-tagged proteins, multiple orthogonal localization methods, replicated across multiple expression conditions","pmids":["9768845"],"is_preprint":false},{"year":2002,"finding":"Dendritic localization of CaMKIIα mRNA (via its 3'UTR signal) is required for normal postsynaptic density targeting of the protein; disrupting dendritic mRNA localization dramatically reduces CaMKIIα in PSDs and impairs late-phase LTP, spatial memory, fear conditioning, and object recognition memory.","method":"Knock-in mouse with mutated endogenous CaMKIIα 3'UTR, PSD fractionation, LTP electrophysiology, behavioral testing","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with multiple orthogonal readouts (biochemistry, electrophysiology, behavior), widely replicated concept","pmids":["12408852"],"is_preprint":false},{"year":2005,"finding":"CaMKIIα enhances the desensitization of NR2B-containing NMDA receptors in an autophosphorylation-dependent manner; kinase-dead (K42R) and autophosphorylation-deficient (T286A) mutants fail to enhance desensitization, and Ca2+ chelation with BAPTA abrogates the effect. CaMKIIα decreases (rather than increases) desensitization of NR2A-containing receptors.","method":"Whole-cell patch-clamp electrophysiology in HEK293 cells co-expressing NMDA receptor subunits and CaMKIIα mutants, BAPTA loading","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution in heterologous cells with active-site and autophosphorylation-site mutagenesis, multiple mutant controls, single lab","pmids":["15866054"],"is_preprint":false},{"year":2008,"finding":"NCAM clustering activates CaMKIIα via Ca2+ influx through associated voltage-dependent Ca2+ channels; activated CaMKIIα forms a complex with NCAM and RPTPα and phosphorylates RPTPα at Ser180/Ser204, increasing RPTPα phosphatase activity, which is required for NCAM-induced neurite outgrowth.","method":"Co-immunoprecipitation, serine phosphorylation assays, dominant-negative RPTPα mutants (S180A/S204A), neurite outgrowth assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, mutagenesis of phosphorylation sites, functional neurite outgrowth readout, single lab with multiple orthogonal methods","pmids":["18809727"],"is_preprint":false},{"year":2009,"finding":"CaMKIIα colocalizes with MUPP1 in the acrosomal region of spermatozoa and selectively binds PDZ domains 10–11 of MUPP1; Ca2+/calmodulin releases CaMKIIα from MUPP1, and competitive displacement of CaMKIIα from these PDZ domains (or CaMKII catalytic inhibition) triggers spontaneous acrosomal exocytosis, indicating CaMKIIα normally suppresses premature acrosomal secretion.","method":"Co-localization, in vitro binding assays mapping PDZ domain specificity, CaMKII inhibitor experiments, acrosomal exocytosis assays in mouse spermatozoa","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding domain mapping plus pharmacological inhibition with functional readout, single lab","pmids":["19934217"],"is_preprint":false},{"year":2009,"finding":"CaMKIIα catalytic domains form paired (autoinhibited) and unpaired (active) conformations in living neurons; glutamate receptor activation triggers a structural transition from paired to unpaired conformation, consistent with a flip-flop switch model of persistent kinase activation.","method":"Fluorescence anisotropy and FRET imaging of Venus-tagged CaMKIIα in neurons, glutamate receptor stimulation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell FRET/anisotropy imaging with receptor stimulation, single lab, conformational model supported by structural prediction","pmids":["19339497"],"is_preprint":false},{"year":2010,"finding":"CaMKIIα selectively translocates to inhibitory (GABAergic) synapses in response to moderate NMDAR activation that triggers GABAAR insertion; Thr286 autophosphorylation is necessary and sufficient to localize CaMKIIα at inhibitory synapses and enhance surface GABAAR expression. Stronger glutamatergic stimulation (coupled to AMPAR insertion) also causes Thr286 autophosphorylation but prevents accumulation at inhibitory synapses via calcineurin.","method":"Fluorescence imaging of CaMKIIα translocation in CA1 neurons, pharmacological NMDAR stimulation paradigms, phosphomimetic/phosphodeficient mutants, calcineurin inhibitor experiments, surface GABAAR quantification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (imaging, mutagenesis, pharmacology, receptor surface expression), mechanistically dissects stimulus-specific targeting","pmids":["21059908"],"is_preprint":false},{"year":2012,"finding":"CaMKIIα interacts with Abi1 under resting conditions through the Abi1 tSNARE domain, which shares homology with the CaMKIIα regulatory domain; this interaction simultaneously inhibits CaMKIIα activity and Abi1-dependent Rac activation. Glutamate receptor activation dissociates the complex via calmodulin binding, and CaMKIIα phosphorylates Abi1 at Ser88 prior to dissociation, contributing to spine maturation.","method":"Co-immunoprecipitation, kinase activity assays, phosphorylation site mutagenesis, Rac activation assays, spine morphology analysis in rat hippocampal neurons","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus kinase activity assay plus spine morphology, single lab, multiple orthogonal methods","pmids":["22993434"],"is_preprint":false},{"year":2013,"finding":"ΔFosB binds the CaMKIIα gene promoter in nucleus accumbens (NAc); chronic fluoxetine reduces ΔFosB binding at the CaMKIIα promoter by inducing histone H3 acetylation decreases and H3K9 dimethylation increases at that locus, suppressing CaMKIIα expression. CaMKII overexpression in NAc blocks fluoxetine's antidepressant effects, while CaMKII inhibition in NAc mimics fluoxetine.","method":"Chromatin immunoprecipitation (ChIP), viral overexpression/inhibition in NAc, chronic social defeat stress paradigm","journal":"Neuropsychopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with functional behavioral validation, single lab, two complementary genetic interventions","pmids":["24240473"],"is_preprint":false},{"year":2013,"finding":"Inactive CaMKIIα constitutively binds the proximal intracellular C-terminal tail of mGluR5 in striatal neurons; Ca2+ activation of CaMKIIα causes its dissociation from mGluR5 and simultaneous recruitment to the adjacent GluN2B subunit of NMDARs, enabling CaMKIIα to phosphorylate GluN2B at a CaMKII-sensitive site.","method":"In vitro pulldown, co-immunoprecipitation in striatal neurons, Ca2+ manipulation, GluN2B phosphorylation assay","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus co-IP in neurons plus phosphorylation assay, single lab","pmids":["24032403"],"is_preprint":false},{"year":2013,"finding":"In neuronal somata, CaMKIIα forms actin-dependent clusters (~1–4 µm) under basal conditions that disperse in a Ca2+-dependent manner within seconds of glutamate/glycine exposure and reform after washout; these clusters are distinct from the dendritic trafficking behavior of CaMKIIα.","method":"Novel recombinant probe (mRNA-display selected) labeling endogenous CaMKIIα in living rat cortical neurons, cytochalasin D actin disruption, Ca2+ imaging","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live-cell imaging of endogenous protein with novel validated probe, pharmacological dissection, single lab","pmids":["24005308"],"is_preprint":false},{"year":2015,"finding":"IRBIT binds to CaMKIIα and suppresses its kinase activity by inhibiting calmodulin binding; IRBIT-deficient mice show elevated CaMKIIα-mediated phosphorylation of tyrosine hydroxylase (TH) in the ventral tegmental area, leading to increased catecholamine levels, hyperlocomotion, and social abnormalities.","method":"Co-immunoprecipitation, in vitro kinase activity assays, calmodulin binding competition assays, IRBIT knockout mice, TH phosphorylation analysis in VTA","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with defined mechanism (calmodulin competition) + in vivo KO with substrate phosphorylation readout, single lab with multiple orthogonal methods","pmids":["25922519"],"is_preprint":false},{"year":2015,"finding":"mTOR activity preserves the poly(A) tail length of CaMKIIα mRNA, preventing its deadenylation; the RNA-stabilizing protein HuD (via its poly(A)-binding third RRM domain) captures CaMKIIα mRNA and promotes its branch-specific dendritic expression, providing a molecular mechanism for synaptic tagging and capture.","method":"mTOR inhibition (rapamycin) in neurons, poly(A) tail assays, HuD overexpression/deletion mutants, dendritic CaMKIIα protein/mRNA quantification","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (rapamycin, poly(A) assay, domain-deletion constructs), single lab","pmids":["25944900"],"is_preprint":false},{"year":2015,"finding":"Elevated CaMKIIα protein in Fmr1 KO cortex causes hyperphosphorylation of long Homer proteins, disrupting mGluR5–Homer scaffolds at synapses; genetic or pharmacological inhibition of CaMKIIα restores mGluR5–Homer scaffolds and rescues circuit hyperexcitability/seizures in Fmr1 KO mice.","method":"CaMKIIα protein level quantification, Homer phosphorylation assays, CaMKIIα inhibitor (KN-93) and genetic inhibition, EEG/circuit excitability recordings in Fmr1 KO mice","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal interventions (pharmacological + genetic), biochemical substrate identification, functional circuit rescue, in vivo model","pmids":["26670047"],"is_preprint":false},{"year":2017,"finding":"A de novo ASD-linked CaMKIIα E183V mutation in the catalytic domain reduces substrate phosphorylation and autophosphorylation, acts as a dominant-negative suppressor of wild-type CaMKIIα autophosphorylation, reduces binding to Shank3, L-type calcium channel subunits, and NMDAR subunits, and increases CaMKIIα turnover. Knock-in mice show reduced synaptic CaMKIIα, lower spine density, decreased excitatory synaptic transmission, hyperactivity, social deficits, and repetitive behaviors.","method":"In vitro kinase assays, co-immunoprecipitation, knock-in mouse model, subcellular fractionation, neuronal morphology analysis, electrophysiology, behavioral testing","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay + mutagenesis + co-IP + in vivo knock-in + electrophysiology + behavior, multiple orthogonal methods in one study","pmids":["28130356"],"is_preprint":false},{"year":2017,"finding":"De novo CAMK2A mutations identified in intellectual disability patients alter CaMKIIα auto-phosphorylation at Thr286 (either increasing or decreasing it), and all mutations affecting auto-phosphorylation also impair neuronal migration, establishing that tightly regulated Thr286 auto-phosphorylation is required for neuronal function and neurodevelopment.","method":"Whole-exome sequencing, biochemical autophosphorylation assays in patient-derived variants, neuronal migration assays","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical functional validation of multiple variants across multiple centers, direct functional (migration) readout, 24 individuals with 19 variants","pmids":["29100089"],"is_preprint":false},{"year":2017,"finding":"A splice-site CAMK2A variant in a neurodevelopmental disorder patient causes exon 11 skipping, deleting the regulatory segment responsible for CaMKII autoinhibition; missense variants predicted to disrupt kinase domain–regulatory segment interactions increase Thr286 phosphorylation in Neuro-2a cells, and a CaMKIIα mutant expressed in hippocampal neurons significantly increases A-type K+ currents, facilitating spike repolarization.","method":"Minigene splicing assay, structural modeling, immunoblotting in Neuro-2a cells, electrophysiology in primary hippocampal neurons","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional splicing assay + cellular phosphorylation assay + electrophysiology, single lab","pmids":["29560374"],"is_preprint":false},{"year":2018,"finding":"The CAMK2A missense mutation p.His477Tyr (in the association/hub domain) is defective in self-oligomerization and unable to assemble into the multimeric holoenzyme; in vivo, it fails to rescue neuronal defects in C. elegans unc-43 mutants, and iPSC-derived neurons from the patient display profound synaptic defects.","method":"Biochemical self-oligomerization assay, C. elegans complementation (unc-43 ortholog), patient iPSC-derived neuron synaptic analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical domain function assay + in vivo ortholog complementation + human iPSC neurons, multiple orthogonal methods","pmids":["29784083"],"is_preprint":false},{"year":2018,"finding":"Activated (Thr286-autophosphorylated) CaMKIIα directly binds the membrane-proximal C-terminal domain of mGlu5a via a tribasic KRR motif (K866-R-R868); mutation of this motif reduces co-immunoprecipitation of CaMKIIα with full-length mGlu5a, and CaMKIIα increases mGlu5a surface expression and modulates the kinetics of mGlu5a-mediated Ca2+ mobilization.","method":"In vitro pulldown with purified proteins, co-immunoprecipitation in heterologous cells, site-directed mutagenesis (KRR→AAA), cell-surface biotinylation, Ca2+ fluorimetry and single-cell Ca2+ imaging","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with purified proteins + mutagenesis + co-IP + functional Ca2+ assay, single lab with multiple orthogonal methods","pmids":["30282777"],"is_preprint":false},{"year":2020,"finding":"GHB analogs bind selectively to the CaMKIIα hub domain at a site revealed by a 2.2-Å X-ray crystal structure; binding promotes concentration-dependent increases in hub thermal stability and provides significant neuroprotection selectively under pathological CaMKIIα hyperactivation (excitotoxicity and cerebral ischemia), establishing the hub domain as a pharmacologically targetable site.","method":"Photoaffinity labeling, chemical proteomics, X-ray crystallography (2.2 Å), differential scanning fluorimetry (thermal stability), in vitro excitotoxicity assays, MCAO mouse model","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure + photoaffinity labeling + functional neuroprotection in vitro and in vivo, multiple orthogonal methods in one study","pmids":["34330837"],"is_preprint":false},{"year":2020,"finding":"Under basal conditions CaMKIIα is recruited to the Shank3 subcompartment of the PSD via phase separation; Ca2+ rise induces GluN2B-mediated recruitment of active CaMKIIα forming CaMKIIα/GluN2B/PSD-95 condensates that autonomously disperse upon Ca2+ removal. Protein phosphatases control Ca2+-dependent shuttling of CaMKIIα between PSD nano-domains, and CaMKIIα activation further enlarges PSD assembly and induces structural LTP.","method":"Phase separation assays, live-cell imaging, FRAP, co-immunoprecipitation, phosphatase inhibitor experiments, structural LTP induction","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple imaging and biochemical methods for phase separation and condensate dynamics, single lab","pmids":["33235361"],"is_preprint":false},{"year":2020,"finding":"Shank3 directly binds activated CaMKIIα between residues 829–1130 of Shank3; mutation of Shank3 residues 949RRK951 to alanines abolishes CaMKII binding in vitro and in cells. This CaMKII–Shank3 interaction, together with Shank3–LTCC interaction, is required for depolarization-induced CREB phosphorylation and c-Fos expression in hippocampal neurons (long-range plasma membrane–to–nucleus signaling).","method":"Co-immunoprecipitation from mouse forebrain, in vitro direct binding with purified proteins, alanine substitution mutagenesis, shRNA/rescue in hippocampal neurons, nuclear CREB phosphorylation and c-Fos assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro reconstitution + mutagenesis + co-IP from brain + shRNA/rescue with functional nuclear signaling readout, single lab with multiple orthogonal methods","pmids":["32019829"],"is_preprint":false},{"year":2020,"finding":"CaMKIIα phosphorylates GluN2A at Ser1459 in response to synaptic activity mimicking LTP; Ser1459 phosphorylation promotes GluN2A interaction with the SNX27-retromer complex, enhancing endosomal recycling of GluN2A-NMDARs to the neuronal surface. Loss of CaMKIIα function blocks the glycine-induced increase in surface GluN2A-NMDARs.","method":"In vitro kinase assay, phosphorylation site mutagenesis, co-immunoprecipitation, SNX27 knockdown, surface NMDAR quantification, synaptic current recordings","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro phosphorylation + mutagenesis + co-IP + surface receptor trafficking assay + electrophysiology, independently replicated in companion paper (PMID:34233182)","pmids":["32877683","34233182"],"is_preprint":false},{"year":2020,"finding":"CaMKIIα holoenzyme stability is characterized by differential domain stability: the kinase domain alone is thermally unstable (Tm ~36°C), stabilized moderately by ATP/MgCl2 (Tm ~40°C) and markedly by the regulatory segment (Tm ~60°C); the hub domain alone is highly stable (Tm ~90°C); within the holoenzyme the kinase domain is stabilized and the hub domain is destabilized. A crystal structure of the kinase domain bound to p-coumaric acid reveals solvent-exposed hydrophobic residues in the substrate-binding pocket in the absence of regulatory segment.","method":"Differential scanning calorimetry (DSC), X-ray crystallography, mass photometry","journal":"Protein science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure + DSC + mass photometry in single study with multiple orthogonal biophysical methods","pmids":["32282091"],"is_preprint":false},{"year":2014,"finding":"CaMKIIα phosphorylates the P2X3 receptor at Thr388 in the C-terminus; this phosphorylation increases P2X3 receptor binding to caveolin-1, and CaMKIIα cooperates with caveolin-1 to drive ATP-induced membrane insertion of P2X3 (and co-insertion of P2X2/P2X3) receptors, increasing surface P2X3 signaling.","method":"Mutagenesis of Thr388, in vitro kinase assay, co-immunoprecipitation, caveolin-1 knockdown, surface receptor trafficking assay in HEK293T cells and primary sensory neurons","journal":"Journal of molecular cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay + mutagenesis + co-IP + caveolin-1 KD + trafficking assay, single lab with multiple orthogonal methods","pmids":["24755854"],"is_preprint":false},{"year":2017,"finding":"S-nitrosation of CaMKIIα (at Cys280/Cys289) promotes its synaptosomal accumulation; GSNOR (S-nitrosoglutathione reductase) overexpression in neurons decreases CaMKIIα S-nitrosation and reduces CaMKIIα in synaptosomal fractions along with downstream p(S831)-GluR1, impairing LTP and cognition. Mutation of the S-nitrosation sites (C280/C289) recapitulates reduced synaptosomal accumulation.","method":"S-nitrosation site mutagenesis, synaptosomal fractionation, GSNOR transgenic/KO mice, LTP electrophysiology, behavioral testing","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site mutagenesis + fractionation + in vivo transgenic/KO models, single lab","pmids":["28883020"],"is_preprint":false},{"year":2018,"finding":"Non-canonical Wnt-3a signals through Frizzled-6/DVL-2/syndecan-4 to recruit CaMKIIα to syndecan-4; CaMKIIα phosphorylates B-raf in vitro and in vivo, activating ERK1/2 signaling and driving chondrocyte de-differentiation.","method":"Co-immunoprecipitation, in vitro kinase assay demonstrating CaMKIIα phosphorylation of B-raf, siRNA knockdown, ERK1/2 activation assays","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay + co-IP + functional de-differentiation assay, single lab","pmids":["29352270"],"is_preprint":false},{"year":2020,"finding":"CAMK2A phosphorylates EZH2 at T487 in a kinase-dependent manner, suppressing EZH2 methyltransferase activity and reducing H3K27me3 and EZH2 occupancy at the SOX2 locus, leading to epigenetic de-repression of SOX2 and support of tumor-initiating cell phenotypes in lung adenocarcinoma.","method":"Kinase-dependent phosphorylation assay, ChIP for H3K27me3 and EZH2, in vitro and in vivo tumor-initiating cell assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation assay + ChIP + functional rescue, single lab","pmids":["32483123"],"is_preprint":false},{"year":2021,"finding":"PDSS1, via its catalytic product CoQ10 and elevation of intracellular calcium, induces CAMK2A phosphorylation (activation), which is required for STAT3 phosphorylation in the cytoplasm; phosphorylated STAT3 then translocates to the nucleus to promote oncogenic signaling and TNBC metastasis. A catalytically inactive PDSS1 mutant fails to activate CAMK2A.","method":"PDSS1 knockdown, catalytic mutant expression, CAMK2A phosphorylation assays, STAT3 phosphorylation/nuclear translocation assays, in vitro migration/invasion, in vivo metastasis model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic mutant + knockdown + phosphorylation cascade assays, single lab","pmids":["34408002"],"is_preprint":false},{"year":2021,"finding":"GluN2A Ser1459 phosphorylation by CaMKIIα (in response to glycine/LTP stimulation) promotes GluN2A-NMDAR interaction with the SNX27-retromer complex for endosomal recycling; the epilepsy-associated S1459G variant abolishes this interaction, reduces spine density, decreases excitatory transmission, and prolongs NMDAR-mediated synaptic current decay by increasing channel open duration.","method":"In vitro kinase assay, co-immunoprecipitation, SNX27/CaMKIIα knockdown, surface NMDAR quantification, NMDAR single-channel and synaptic current recordings, spine density analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay + mutagenesis + co-IP + electrophysiology + trafficking assay, replicates and extends PMID:32877683 findings","pmids":["34233182"],"is_preprint":false},{"year":2012,"finding":"Bi-directional regulation of CaMKIIα Thr286 autophosphorylation by NMDAR activation: low NMDA concentration (20 µM) up-regulates Thr286 phosphorylation via both NR2A and NR2B, while high concentration (100 µM) causes dephosphorylation via a phosphatase sensitive to high-concentration okadaic acid but not to PP2A or PP2B inhibitors specifically.","method":"Pharmacological NMDAR subunit inhibition and knockdown, NR2A/NR2B overexpression, phosphatase inhibitor profiling, immunoblotting of p-Thr286 in cortical neurons","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and molecular manipulation with multiple controls, single lab","pmids":["22582824"],"is_preprint":false},{"year":2008,"finding":"CaMKIIα and CaMKIIβ co-expressed with NR1/NR2A or NR1/NR2B receptors do not alter the ethanol inhibition of NMDA receptor currents, and deletion of CaMKII binding domains in NR1 or NR2 or phospho-site mutations does not change ethanol sensitivity (negative result).","method":"Whole-cell patch-clamp in HEK293 cells co-expressing CaMKII isoforms and NMDAR subunits, GFP-tagged CaMKII, ethanol concentration-response","journal":"Alcohol","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct electrophysiology in reconstituted system with multiple mutant controls; negative finding well-controlled","pmids":["18562151"],"is_preprint":false},{"year":2024,"finding":"The CaMKIIα hub domain contains a discrete small-molecule binding site; the novel ligand Ph-HTBA binds with mid-nanomolar affinity, induces a CaMKIIα Trp403 flip in the hub, markedly stabilizes the hub thermally, is brain-penetrant in mice (Kp,uu = 0.85), and selectively modulates the hub domain.","method":"Binding affinity assays, thermal shift assay, X-ray crystallography-informed structure-activity relationship, in vivo brain penetration (Kp,uu measurement)","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biochemical binding + thermal stabilization + brain penetration in vivo, structural basis inferred from prior crystal structure, single lab","pmids":["36346645"],"is_preprint":false}],"current_model":"CaMKIIα is a dodecameric (hub domain-assembled) Ca2+/calmodulin-activated Ser/Thr kinase that undergoes autophosphorylation at Thr286 to generate Ca2+-independent autonomous activity; it is targeted to excitatory or inhibitory postsynaptic sites depending on stimulus strength and calcineurin activity, is recruited to the PSD via phase separation involving Shank3 and GluN2B, and phosphorylates a wide array of synaptic substrates—including GluN2A (Ser1459, promoting NMDAR recycling), GluN2B, Homer proteins (disrupting mGluR5 scaffolds when CaMKIIα is elevated), RPTPα (Ser180/204, increasing phosphatase activity downstream of NCAM), B-raf (in non-canonical Wnt signaling), EZH2 (T487, suppressing its methyltransferase activity), and the P2X3 receptor (Thr388, driving membrane insertion)—while its local dendritic translation from dendritically localized mRNA (dependent on its 3'UTR and regulated by Staufen2, mTOR/HuD, and activity) is required for normal PSD delivery and synaptic/behavioral plasticity."},"narrative":{"mechanistic_narrative":"CaMKIIα is a Ca2+/calmodulin-activated Ser/Thr kinase that functions as a central transducer of synaptic activity, converting Ca2+ signals into persistent changes in synaptic strength and structure [PMID:21059908, PMID:29100089]. Its holoenzyme is built from a thermally stable, self-oligomerizing hub domain that assembles the multimeric enzyme and a kinase domain that is autoinhibited by a regulatory segment, with the kinase domain unstable in isolation but markedly stabilized by the regulatory segment within the holoenzyme [PMID:29784083, PMID:32282091]; in living neurons the catalytic domains transition from a paired (autoinhibited) to unpaired (active) conformation upon glutamate receptor activation, a flip-flop switch consistent with persistent activity [PMID:19339497]. Thr286 autophosphorylation gates this autonomous activity and is bi-directionally tuned by NMDAR-driven Ca2+ and opposing phosphatases [PMID:22582824], and tightly regulated Thr286 phosphorylation is required for neuronal migration and function [PMID:29100089]. Activity recruits CaMKIIα into the postsynaptic density through phase separation with Shank3 and Ca2+-dependent, GluN2B-mediated condensate formation with PSD-95, enabling structural LTP [PMID:33235361, PMID:32019829], and stimulus strength together with calcineurin directs CaMKIIα to either excitatory or inhibitory synapses to control receptor surface expression [PMID:21059908]. Once positioned, CaMKIIα phosphorylates a broad substrate set to remodel synaptic signaling: GluN2A at Ser1459 to promote SNX27-retromer–dependent NMDAR recycling [PMID:32877683, PMID:34233182], GluN2B [PMID:24032403], long Homer proteins to control mGluR5 scaffolds [PMID:26670047], and RPTPα at Ser180/Ser204 downstream of NCAM to drive neurite outgrowth [PMID:18809727]. Its function depends on dendritic localization of its own 3'UTR-bearing mRNA, whose stability and branch-specific translation are governed by mTOR and HuD; disrupting dendritic mRNA targeting depletes synaptic CaMKIIα and impairs late-phase LTP and memory [PMID:12408852, PMID:25944900]. De novo CAMK2A mutations that alter catalytic activity, Thr286 autophosphorylation, regulatory-segment autoinhibition, or hub-domain oligomerization cause autism, intellectual disability, and neurodevelopmental disorders [PMID:28130356, PMID:29100089, PMID:29560374, PMID:29784083]. Beyond the nervous system, CaMKIIα also acts in non-canonical Wnt signaling by phosphorylating B-raf [PMID:29352270], in lung adenocarcinoma by phosphorylating EZH2 at T487 to de-repress SOX2 [PMID:32483123], and in TNBC metastasis downstream of PDSS1/CoQ10 to drive STAT3 signaling [PMID:34408002]. The hub domain is a pharmacologically targetable site bound by GHB analogs that confer neuroprotection under pathological hyperactivation [PMID:34330837, PMID:36346645].","teleology":[{"year":1998,"claim":"Established how the predominantly cytosolic CaMKIIα is anchored at synaptic actin, showing that subcellular targeting is supplied in trans by the actin-binding CaMKIIβ isoform via hetero-oligomerization.","evidence":"GFP-tagged isoform live imaging and co-expression with F-actin co-localization in neurons","pmids":["9768845"],"confidence":"High","gaps":["Does not address how the holoenzyme is recruited specifically to the PSD","Stoichiometry of α/β in native holoenzymes not resolved"]},{"year":2002,"claim":"Demonstrated that dendritic mRNA localization, not just protein, is required for synaptic CaMKIIα function, linking a 3'UTR-encoded RNA transport signal to PSD targeting, LTP and memory.","evidence":"Knock-in mouse with mutated endogenous 3'UTR, PSD fractionation, LTP electrophysiology, behavior","pmids":["12408852"],"confidence":"High","gaps":["RNA-binding factors mediating localization not identified here","Local versus somatic translation contribution not separated"]},{"year":2005,"claim":"Showed CaMKIIα has subunit-selective effects on NMDAR gating, decreasing NR2A but enhancing NR2B desensitization in an autophosphorylation- and Ca2+-dependent manner, distinguishing substrate-specific receptor regulation.","evidence":"Whole-cell patch-clamp in HEK293 with NMDAR subunits and K42R/T286A mutants, BAPTA loading","pmids":["15866054"],"confidence":"High","gaps":["Heterologous system may not reflect native PSD context","Phosphorylation sites mediating the effect not mapped"]},{"year":2008,"claim":"Identified RPTPα as a CaMKIIα substrate downstream of NCAM, defining a kinase-phosphatase relay in which CaMKIIα phosphorylation increases RPTPα activity to drive neurite outgrowth.","evidence":"Reciprocal co-IP, Ser180/Ser204 phosphorylation assays, S180A/S204A mutants, neurite outgrowth","pmids":["18809727"],"confidence":"High","gaps":["In vivo relevance for axon guidance not tested","Single lab"]},{"year":2009,"claim":"Resolved the conformational basis of persistent activation by directly imaging a paired-to-unpaired catalytic domain transition in neurons upon receptor stimulation.","evidence":"Fluorescence anisotropy and FRET imaging of Venus-tagged CaMKIIα with glutamate stimulation","pmids":["19339497"],"confidence":"Medium","gaps":["Model relies on structural prediction; atomic confirmation not provided","Relationship to Thr286 autophosphorylation not directly linked"]},{"year":2009,"claim":"Revealed a non-neuronal autoinhibitory role in sperm: CaMKIIα sequestered on MUPP1 PDZ domains suppresses premature acrosomal exocytosis until Ca2+/CaM releases it.","evidence":"Co-localization, PDZ domain binding mapping, CaMKII inhibition, acrosomal exocytosis assays in mouse sperm","pmids":["19934217"],"confidence":"Medium","gaps":["Direct exocytosis substrate of CaMKIIα not identified","Single lab"]},{"year":2012,"claim":"Established bi-directional control of Thr286 autophosphorylation by NMDAR signal strength, with low Ca2+ promoting and high Ca2+ triggering phosphatase-mediated dephosphorylation.","evidence":"Pharmacological NMDAR subunit manipulation, phosphatase inhibitor profiling, p-Thr286 immunoblotting in cortical neurons","pmids":["22582824"],"confidence":"Medium","gaps":["Identity of the high-OA-sensitive phosphatase not defined","Mechanistic basis for concentration switch unresolved"]},{"year":2012,"claim":"Identified Abi1 as a resting-state binding partner whose tSNARE domain mimics the CaMKIIα regulatory segment, mutually inhibiting kinase and Rac signaling until Ca2+ dissociates the complex during spine maturation.","evidence":"Co-IP, kinase activity assays, Ser88 phospho-site mutagenesis, Rac assays, spine morphology in hippocampal neurons","pmids":["22993434"],"confidence":"Medium","gaps":["In vivo role in spine maturation not tested","Single lab"]},{"year":2013,"claim":"Defined an mGluR5→GluN2B switch in which Ca2+ activation releases CaMKIIα from mGluR5 and recruits it to GluN2B for phosphorylation, coupling metabotropic and ionotropic receptor signaling.","evidence":"Pulldown, co-IP in striatal neurons, Ca2+ manipulation, GluN2B phosphorylation assay","pmids":["24032403"],"confidence":"Medium","gaps":["GluN2B phospho-site not mapped here","Functional plasticity consequence not measured"]},{"year":2013,"claim":"Characterized rapid, actin-dependent somatic clustering of endogenous CaMKIIα that disperses with Ca2+, distinguishing somatic dynamics from dendritic trafficking.","evidence":"mRNA-display-selected recombinant probe imaging in living cortical neurons, cytochalasin D, Ca2+ imaging","pmids":["24005308"],"confidence":"Medium","gaps":["Functional purpose of somatic clusters unknown","Single lab"]},{"year":2013,"claim":"Linked CaMKIIα expression to mood-related circuitry, showing ΔFosB epigenetic control of the CaMKIIα promoter in NAc determines antidepressant responses.","evidence":"ChIP, viral overexpression/inhibition in NAc, chronic social defeat stress","pmids":["24240473"],"confidence":"Medium","gaps":["Downstream NAc substrates of CaMKII not defined","Causal histone marks not separated from ΔFosB binding"]},{"year":2014,"claim":"Extended CaMKIIα substrate range to the pain receptor P2X3, identifying Thr388 phosphorylation that promotes caveolin-1–dependent membrane insertion.","evidence":"Thr388 mutagenesis, in vitro kinase assay, co-IP, caveolin-1 knockdown, surface trafficking in HEK293T and sensory neurons","pmids":["24755854"],"confidence":"High","gaps":["In vivo nociceptive role not established here","Single lab"]},{"year":2015,"claim":"Identified IRBIT as a calmodulin-competitive inhibitor of CaMKIIα, with loss causing excess TH phosphorylation and dopaminergic behavioral abnormalities, defining an endogenous brake on kinase activity.","evidence":"Co-IP, in vitro kinase and CaM-competition assays, IRBIT KO mice, TH phosphorylation in VTA","pmids":["25922519"],"confidence":"High","gaps":["Direct TH phospho-site by CaMKIIα not mapped","Single lab"]},{"year":2015,"claim":"Defined the mTOR/HuD axis that stabilizes CaMKIIα mRNA poly(A) tails and drives branch-specific dendritic expression, providing a molecular basis for synaptic tagging and capture.","evidence":"Rapamycin treatment, poly(A) tail assays, HuD domain-deletion mutants, dendritic mRNA/protein quantification","pmids":["25944900"],"confidence":"Medium","gaps":["Link to in vivo plasticity not tested here","Single lab"]},{"year":2015,"claim":"Showed that pathological elevation of CaMKIIα hyperphosphorylates Homer to disrupt mGluR5 scaffolds, and that CaMKIIα inhibition rescues Fragile X circuit hyperexcitability.","evidence":"Protein quantification, Homer phosphorylation, KN-93 and genetic inhibition, EEG in Fmr1 KO mice","pmids":["26670047"],"confidence":"High","gaps":["Homer phospho-sites not mapped","Whether elevated CaMKIIα is cause or consequence in other disease contexts unclear"]},{"year":2017,"claim":"Connected CaMKIIα to disease by showing the ASD-linked E183V catalytic mutation acts dominant-negatively, reduces partner binding, and produces synaptic and behavioral deficits in knock-in mice.","evidence":"In vitro kinase assays, co-IP, knock-in mouse, fractionation, morphology, electrophysiology, behavior","pmids":["28130356"],"confidence":"High","gaps":["Mechanism of accelerated turnover not defined","Generalizability to other catalytic variants untested"]},{"year":2017,"claim":"Established CAMK2A as a neurodevelopmental disorder gene, showing that bidirectional dysregulation of Thr286 autophosphorylation impairs neuronal migration.","evidence":"Whole-exome sequencing, biochemical autophosphorylation assays of variants, neuronal migration assays","pmids":["29100089"],"confidence":"High","gaps":["Substrate(s) controlling migration not identified","Why both gain and loss of Thr286 phosphorylation are pathogenic not mechanistically resolved"]},{"year":2017,"claim":"Defined a synaptic targeting function for CaMKIIα Cys280/Cys289 S-nitrosation, which promotes synaptosomal accumulation and downstream GluR1 phosphorylation needed for LTP.","evidence":"S-nitrosation site mutagenesis, synaptosomal fractionation, GSNOR transgenic/KO mice, LTP, behavior","pmids":["28883020"],"confidence":"Medium","gaps":["Structural effect of nitrosation on holoenzyme not resolved","Single lab"]},{"year":2017,"claim":"Linked regulatory-segment integrity to disease, showing exon 11 skipping deletes the autoinhibitory segment and missense variants increase Thr286 phosphorylation and alter A-type K+ currents.","evidence":"Minigene splicing assay, structural modeling, Neuro-2a immunoblotting, hippocampal neuron electrophysiology","pmids":["29560374"],"confidence":"Medium","gaps":["Mechanism linking hyperactive CaMKIIα to K+ current change not defined","Single lab"]},{"year":2018,"claim":"Established the hub domain's essential oligomerization role by showing the His477Tyr variant cannot assemble the holoenzyme and fails to support neuronal function across worm and human iPSC models.","evidence":"Self-oligomerization assay, C. elegans unc-43 complementation, patient iPSC-derived neurons","pmids":["29784083"],"confidence":"High","gaps":["Quantitative relationship between assembly defect and synaptic deficit not resolved","Single variant"]},{"year":2018,"claim":"Mapped the structural basis of CaMKIIα–mGlu5 coupling, showing activated CaMKIIα binds a tribasic KRR motif and increases mGlu5 surface expression and Ca2+ signaling kinetics.","evidence":"Pulldown with purified proteins, co-IP, KRR→AAA mutagenesis, surface biotinylation, Ca2+ imaging","pmids":["30282777"],"confidence":"High","gaps":["In vivo synaptic consequence not tested","Single lab"]},{"year":2018,"claim":"Extended CaMKIIα to non-canonical Wnt signaling, identifying B-raf as a substrate that activates ERK1/2 to drive chondrocyte de-differentiation.","evidence":"Co-IP, in vitro B-raf phosphorylation, siRNA, ERK1/2 activation assays","pmids":["29352270"],"confidence":"Medium","gaps":["B-raf phospho-site not mapped","Single lab"]},{"year":2020,"claim":"Provided biophysical architecture of the holoenzyme, quantifying domain-specific thermal stability and how the regulatory segment stabilizes the kinase while the hub is destabilized in context.","evidence":"Differential scanning calorimetry, X-ray crystallography, mass photometry","pmids":["32282091"],"confidence":"High","gaps":["Functional consequence of reciprocal stabilization not tested in cells","Single lab"]},{"year":2020,"claim":"Demonstrated that CaMKIIα is recruited to the PSD by phase separation with Shank3 and forms Ca2+-dependent GluN2B/PSD-95 condensates that drive structural LTP, with phosphatases controlling nano-domain shuttling.","evidence":"Phase separation assays, live imaging, FRAP, co-IP, phosphatase inhibitors, structural LTP","pmids":["33235361"],"confidence":"Medium","gaps":["In vivo verification of condensates lacking","Single lab"]},{"year":2020,"claim":"Mapped direct Shank3–CaMKIIα binding (Shank3 949RRK951) and showed it enables depolarization-induced membrane-to-nucleus CREB/c-Fos signaling.","evidence":"Co-IP from forebrain, in vitro binding, alanine mutagenesis, shRNA/rescue, CREB phosphorylation and c-Fos assays","pmids":["32019829"],"confidence":"High","gaps":["Mechanism transmitting signal to nucleus not fully defined","Single lab"]},{"year":2020,"claim":"Identified GluN2A Ser1459 as a CaMKIIα substrate that recruits the SNX27-retromer to recycle GluN2A-NMDARs to the surface during LTP, replicated and extended in a companion study including an epilepsy variant.","evidence":"In vitro kinase assay, phospho-site mutagenesis, co-IP, SNX27 knockdown, surface NMDAR quantification, electrophysiology","pmids":["32877683","34233182"],"confidence":"High","gaps":["Other retromer cargoes regulated by CaMKIIα unknown","In vivo memory consequence of S1459 phosphorylation not tested"]},{"year":2020,"claim":"Revealed a cancer kinase function: CaMKIIα phosphorylates EZH2 at T487 to suppress its methyltransferase activity, de-repressing SOX2 and supporting tumor-initiating cells in lung adenocarcinoma.","evidence":"Phosphorylation assay, ChIP for H3K27me3/EZH2, tumor-initiating cell assays in vitro and in vivo","pmids":["32483123"],"confidence":"Medium","gaps":["Upstream activator of CaMKIIα in tumors not defined here","Single lab"]},{"year":2021,"claim":"Placed CaMKIIα in a metabolic-oncogenic cascade, showing PDSS1/CoQ10-driven Ca2+ activates CaMKIIα to phosphorylate STAT3 and promote TNBC metastasis.","evidence":"PDSS1 knockdown, catalytic mutant, CaMKIIα and STAT3 phosphorylation assays, metastasis model","pmids":["34408002"],"confidence":"Medium","gaps":["Direct STAT3 phospho-site by CaMKIIα not mapped","Single lab"]},{"year":2021,"claim":"Established the hub domain as a druggable allosteric site, solving a crystal structure of GHB-analog binding that thermally stabilizes the hub and confers neuroprotection selectively under hyperactivation.","evidence":"Photoaffinity labeling, chemical proteomics, 2.2-Å X-ray structure, DSF, excitotoxicity and MCAO models","pmids":["34330837"],"confidence":"High","gaps":["Mechanism linking hub stabilization to reduced pathological activity not fully defined","Selectivity over other CaMKII isoforms not detailed"]},{"year":2024,"claim":"Advanced hub-domain pharmacology with a brain-penetrant ligand (Ph-HTBA) that binds at mid-nanomolar affinity and induces a Trp403 conformational flip, validating the hub as a tractable CNS target.","evidence":"Binding affinity, thermal shift, SAR informed by crystallography, in vivo brain penetration (Kp,uu)","pmids":["36346645"],"confidence":"Medium","gaps":["Therapeutic efficacy in disease models not shown here","Functional kinase consequence of Trp403 flip not defined"]},{"year":null,"claim":"How the diverse substrate phosphorylation events, condensate dynamics, and bidirectional Thr286 regulation are integrated to encode specific synaptic and behavioral plasticity outcomes in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified in vivo map linking individual substrate phosphorylations to plasticity readouts","Mechanism distinguishing physiological vs pathological hyperactivation incompletely defined","Substrate selectivity rules for the activated holoenzyme not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,9,13,22,24,26,27,29]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[3,15,22,24,27]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,11,7]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,10]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,10]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,10]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,18,24]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,6,20,22,29]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,18,26,28]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,14,15,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[13,14,15,27,28,29]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[27]}],"complexes":["CaMKII holoenzyme (dodecameric hub-assembled)","CaMKIIα/GluN2B/PSD-95 condensate","NCAM/RPTPα/CaMKIIα complex"],"partners":["SHANK3","GRIN2B","GRM5","PTPRA","MPDZ","ABI1","DLG4","EZH2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UQM7","full_name":"Calcium/calmodulin-dependent protein kinase type II subunit alpha","aliases":[],"length_aa":478,"mass_kda":54.1,"function":"Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in various processes, such as synaptic plasticity, neurotransmitter release and long-term potentiation (PubMed:14722083). Member of the NMDAR signaling complex in excitatory synapses, it regulates NMDAR-dependent potentiation of the AMPAR and therefore excitatory synaptic transmission (By similarity). Regulates dendritic spine development (PubMed:28130356). Also regulates the migration of developing neurons (PubMed:29100089). Phosphorylates the transcription factor FOXO3 to activate its transcriptional activity (PubMed:23805378). Phosphorylates the transcription factor ETS1 in response to calcium signaling, thereby decreasing ETS1 affinity for DNA (By similarity). In response to interferon-gamma (IFN-gamma) stimulation, catalyzes phosphorylation of STAT1, stimulating the JAK-STAT signaling pathway (PubMed:11972023). In response to interferon-beta (IFN-beta) stimulation, stimulates the JAK-STAT signaling pathway (PubMed:35568036). In response to interferon-gamma (IFN-gamma) stimulation, catalyzes phosphorylation of PSAT1, inhibiting ferroptosis by promoting GPX4 hydroxylation and stability (PubMed:40281343). Acts as a negative regulator of 2-arachidonoylglycerol (2-AG)-mediated synaptic signaling via modulation of DAGLA activity (By similarity)","subcellular_location":"Synapse; Postsynaptic density; Cell projection, dendritic spine; Cell projection, dendrite","url":"https://www.uniprot.org/uniprotkb/Q9UQM7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CAMK2A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CAMK2A","total_profiled":1310},"omim":[{"mim_id":"621415","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 77; MRD77","url":"https://www.omim.org/entry/621415"},{"mim_id":"618095","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 63; MRT63","url":"https://www.omim.org/entry/618095"},{"mim_id":"617799","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 54; MRD54","url":"https://www.omim.org/entry/617799"},{"mim_id":"617798","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 53; MRD53","url":"https://www.omim.org/entry/617798"},{"mim_id":"614453","title":"LEUCINE-RICH REPEAT-CONTAINING PROTEIN 7; LRRC7","url":"https://www.omim.org/entry/614453"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Plasma membrane","reliability":"Uncertain"},{"location":"Primary cilium tip","reliability":"Uncertain"},{"location":"Primary cilium transition zone","reliability":"Uncertain"},{"location":"Principal piece","reliability":"Uncertain"},{"location":"Cell Junctions","reliability":"Additional"},{"location":"Perinuclear theca","reliability":"Additional"},{"location":"Calyx","reliability":"Additional"},{"location":"Connecting piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":486.6},{"tissue":"skeletal muscle","ntpm":153.5}],"url":"https://www.proteinatlas.org/search/CAMK2A"},"hgnc":{"alias_symbol":["KIAA0968","CaMKIINalpha","CaMKIIα"],"prev_symbol":["CAMKA"]},"alphafold":{"accession":"Q9UQM7","domains":[{"cath_id":"3.30.200.20","chopping":"6-89","consensus_level":"high","plddt":91.2758,"start":6,"end":89},{"cath_id":"1.10.510.10","chopping":"94-161_176-282","consensus_level":"high","plddt":96.0085,"start":94,"end":282},{"cath_id":"3.10.450.50","chopping":"343-470","consensus_level":"high","plddt":86.1852,"start":343,"end":470}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQM7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQM7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQM7-F1-predicted_aligned_error_v6.png","plddt_mean":85.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CAMK2A","jax_strain_url":"https://www.jax.org/strain/search?query=CAMK2A"},"sequence":{"accession":"Q9UQM7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UQM7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UQM7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQM7"}},"corpus_meta":[{"pmid":"12408852","id":"PMC_12408852","title":"Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation.","date":"2002","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/12408852","citation_count":418,"is_preprint":false},{"pmid":"9768845","id":"PMC_9768845","title":"CaMKIIbeta functions as an F-actin targeting module that localizes CaMKIIalpha/beta heterooligomers to dendritic spines.","date":"1998","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/9768845","citation_count":283,"is_preprint":false},{"pmid":"11668676","id":"PMC_11668676","title":"A CamKIIalpha iCre BAC allows brain-specific gene inactivation.","date":"2001","source":"Genesis (New York, N.Y. : 2000)","url":"https://pubmed.ncbi.nlm.nih.gov/11668676","citation_count":255,"is_preprint":false},{"pmid":"21068402","id":"PMC_21068402","title":"MicroRNA-148/152 impair innate response and antigen presentation of TLR-triggered dendritic cells by targeting CaMKIIα.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21068402","citation_count":233,"is_preprint":false},{"pmid":"23632380","id":"PMC_23632380","title":"Distribution of CaMKIIα expression in the brain in vivo, studied by CaMKIIα-GFP mice.","date":"2013","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/23632380","citation_count":179,"is_preprint":false},{"pmid":"29100089","id":"PMC_29100089","title":"De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability.","date":"2017","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29100089","citation_count":153,"is_preprint":false},{"pmid":"30220561","id":"PMC_30220561","title":"LncRNA CamK-A Regulates Ca2+-Signaling-Mediated Tumor Microenvironment Remodeling.","date":"2018","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/30220561","citation_count":136,"is_preprint":false},{"pmid":"21059908","id":"PMC_21059908","title":"Selective translocation of Ca2+/calmodulin protein kinase IIalpha (CaMKIIalpha) to inhibitory synapses.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21059908","citation_count":118,"is_preprint":false},{"pmid":"28130356","id":"PMC_28130356","title":"A Novel Human CAMK2A Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors.","date":"2017","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28130356","citation_count":90,"is_preprint":false},{"pmid":"21869818","id":"PMC_21869818","title":"Independent localization of MAP2, CaMKIIα and β-actin RNAs in low copy numbers.","date":"2011","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/21869818","citation_count":87,"is_preprint":false},{"pmid":"24240473","id":"PMC_24240473","title":"Fluoxetine epigenetically alters the CaMKIIα promoter in nucleus accumbens to regulate ΔFosB binding and antidepressant effects.","date":"2013","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24240473","citation_count":85,"is_preprint":false},{"pmid":"29560374","id":"PMC_29560374","title":"De novo variants in CAMK2A and CAMK2B cause neurodevelopmental disorders.","date":"2018","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/29560374","citation_count":70,"is_preprint":false},{"pmid":"33235361","id":"PMC_33235361","title":"CaMKIIα-driven, phosphatase-checked postsynaptic plasticity via phase separation.","date":"2020","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/33235361","citation_count":69,"is_preprint":false},{"pmid":"19339497","id":"PMC_19339497","title":"Structural rearrangement of CaMKIIalpha catalytic domains encodes activation.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19339497","citation_count":69,"is_preprint":false},{"pmid":"32522211","id":"PMC_32522211","title":"Extrasynaptic CaMKIIα is involved in the antidepressant effects of ketamine by downregulating GluN2B receptors in an LPS-induced depression model.","date":"2020","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/32522211","citation_count":68,"is_preprint":false},{"pmid":"29784083","id":"PMC_29784083","title":"A homozygous loss-of-function CAMK2A mutation causes growth delay, frequent seizures and severe intellectual disability.","date":"2018","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/29784083","citation_count":61,"is_preprint":false},{"pmid":"15866054","id":"PMC_15866054","title":"CaMKIIalpha enhances the desensitization of NR2B-containing NMDA receptors by an autophosphorylation-dependent mechanism.","date":"2005","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/15866054","citation_count":59,"is_preprint":false},{"pmid":"29133437","id":"PMC_29133437","title":"Abnormal Microglia and Enhanced Inflammation-Related Gene Transcription in Mice with Conditional Deletion of Ctcf in Camk2a-Cre-Expressing Neurons.","date":"2017","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29133437","citation_count":55,"is_preprint":false},{"pmid":"36963833","id":"PMC_36963833","title":"CaMKIIα Promoter-Controlled Circuit Manipulations Target Both Pyramidal Cells and Inhibitory Interneurons in Cortical Networks.","date":"2023","source":"eNeuro","url":"https://pubmed.ncbi.nlm.nih.gov/36963833","citation_count":55,"is_preprint":false},{"pmid":"15548423","id":"PMC_15548423","title":"One-trial aversive learning induces late changes in hippocampal CaMKIIalpha, Homer 1a, Syntaxin 1a and ERK2 protein levels.","date":"2004","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/15548423","citation_count":51,"is_preprint":false},{"pmid":"31016106","id":"PMC_31016106","title":"Inhibition of CaMKIIα Activity Enhances Antitumor Effect of Fullerene C60 Nanocrystals by Suppression of Autophagic Degradation.","date":"2019","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/31016106","citation_count":47,"is_preprint":false},{"pmid":"32877683","id":"PMC_32877683","title":"An Epilepsy-Associated GRIN2A Rare Variant Disrupts CaMKIIα Phosphorylation of GluN2A and NMDA Receptor Trafficking.","date":"2020","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/32877683","citation_count":46,"is_preprint":false},{"pmid":"30148677","id":"PMC_30148677","title":"Hypoxic preconditioning attenuates necroptotic neuronal death induced by global cerebral ischemia via Drp1-dependent signaling pathway mediated by CaMKIIα inactivation in adult rats.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/30148677","citation_count":46,"is_preprint":false},{"pmid":"29615706","id":"PMC_29615706","title":"Analysis of the CaMKIIα and β splice-variant distribution among brain regions reveals isoform-specific differences in holoenzyme formation.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29615706","citation_count":46,"is_preprint":false},{"pmid":"19925620","id":"PMC_19925620","title":"Kynurenate derivative attenuates the nitroglycerin-induced CamKIIα and CGRP expression changes.","date":"2009","source":"Headache","url":"https://pubmed.ncbi.nlm.nih.gov/19925620","citation_count":45,"is_preprint":false},{"pmid":"26670047","id":"PMC_26670047","title":"Elevated CaMKIIα and Hyperphosphorylation of Homer Mediate Circuit Dysfunction in a Fragile X Syndrome Mouse Model.","date":"2015","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26670047","citation_count":45,"is_preprint":false},{"pmid":"32760495","id":"PMC_32760495","title":"Nrf2 promotes esophageal squamous cell carcinoma (ESCC) resistance to radiotherapy through the CaMKIIα-associated activation of autophagy.","date":"2020","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/32760495","citation_count":45,"is_preprint":false},{"pmid":"34330837","id":"PMC_34330837","title":"GHB analogs confer neuroprotection through specific interaction with the CaMKIIα hub domain.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34330837","citation_count":42,"is_preprint":false},{"pmid":"31889960","id":"PMC_31889960","title":"The novel circular RNA circ-CAMK2A enhances lung adenocarcinoma metastasis by regulating the miR-615-5p/fibronectin 1 pathway.","date":"2019","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31889960","citation_count":40,"is_preprint":false},{"pmid":"24032403","id":"PMC_24032403","title":"Differential regulation of CaMKIIα interactions with mGluR5 and NMDA receptors by Ca(2+) in neurons.","date":"2013","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24032403","citation_count":40,"is_preprint":false},{"pmid":"25944900","id":"PMC_25944900","title":"Mammalian Target of Rapamycin (mTOR) Tagging Promotes Dendritic Branch Variability through the Capture of Ca2+/Calmodulin-dependent Protein Kinase II α (CaMKIIα) mRNAs by the RNA-binding Protein HuD.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25944900","citation_count":39,"is_preprint":false},{"pmid":"18809727","id":"PMC_18809727","title":"NCAM induces CaMKIIalpha-mediated RPTPalpha phosphorylation to enhance its catalytic activity and neurite outgrowth.","date":"2008","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18809727","citation_count":38,"is_preprint":false},{"pmid":"25922519","id":"PMC_25922519","title":"IRBIT regulates CaMKIIα activity and contributes to catecholamine homeostasis through tyrosine hydroxylase phosphorylation.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25922519","citation_count":38,"is_preprint":false},{"pmid":"28883020","id":"PMC_28883020","title":"Increased GSNOR Expression during Aging Impairs Cognitive Function and Decreases S-Nitrosation of CaMKIIα.","date":"2017","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28883020","citation_count":37,"is_preprint":false},{"pmid":"33158963","id":"PMC_33158963","title":"CaMKIIα-Positive Interneurons Identified via a microRNA-Based Viral Gene Targeting Strategy.","date":"2020","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/33158963","citation_count":36,"is_preprint":false},{"pmid":"32019829","id":"PMC_32019829","title":"Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction.","date":"2020","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32019829","citation_count":36,"is_preprint":false},{"pmid":"34408002","id":"PMC_34408002","title":"PDSS1-Mediated Activation of CAMK2A-STAT3 Signaling Promotes Metastasis in Triple-Negative Breast Cancer.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/34408002","citation_count":35,"is_preprint":false},{"pmid":"19934217","id":"PMC_19934217","title":"CaMKIIalpha interacts with multi-PDZ domain protein MUPP1 in spermatozoa and prevents spontaneous acrosomal exocytosis.","date":"2009","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/19934217","citation_count":35,"is_preprint":false},{"pmid":"32508597","id":"PMC_32508597","title":"miR-142-3p Regulates BDNF Expression in Activated Rodent Microglia Through Its Target CAMK2A.","date":"2020","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32508597","citation_count":33,"is_preprint":false},{"pmid":"27842048","id":"PMC_27842048","title":"CaMKIIα underlies spontaneous and evoked pain behaviors in Berkeley sickle cell transgenic mice.","date":"2016","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/27842048","citation_count":32,"is_preprint":false},{"pmid":"32005763","id":"PMC_32005763","title":"SIRT1 Decreases Emotional Pain Vulnerability with Associated CaMKIIα Deacetylation in Central Amygdala.","date":"2020","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32005763","citation_count":32,"is_preprint":false},{"pmid":"35667849","id":"PMC_35667849","title":"GABAergic CaMKIIα+ Amygdala Output Attenuates Pain and Modulates Emotional-Motivational Behavior via Parabrachial Inhibition.","date":"2022","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35667849","citation_count":31,"is_preprint":false},{"pmid":"27604243","id":"PMC_27604243","title":"Beneficial Effects of a CaMKIIα Inhibitor TatCN21 Peptide in Global Cerebral Ischemia.","date":"2016","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/27604243","citation_count":30,"is_preprint":false},{"pmid":"37678540","id":"PMC_37678540","title":"LHPP in Glutamatergic Neurons of the Ventral Hippocampus Mediates Depression-like Behavior by Dephosphorylating CaMKIIα and ERK.","date":"2023","source":"Biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/37678540","citation_count":30,"is_preprint":false},{"pmid":"25404896","id":"PMC_25404896","title":"Elevated activation of CaMKIIα in the CPEB3-knockout hippocampus impairs a specific form of NMDAR-dependent synaptic depotentiation.","date":"2014","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/25404896","citation_count":29,"is_preprint":false},{"pmid":"32483123","id":"PMC_32483123","title":"CAMK2A supported tumor initiating cells of lung adenocarcinoma by upregulating SOX2 through EZH2 phosphorylation.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32483123","citation_count":27,"is_preprint":false},{"pmid":"32248729","id":"PMC_32248729","title":"Rbfox-1 contributes to CaMKIIα expression and intracerebral hemorrhage-induced secondary brain injury via blocking micro-RNA-124.","date":"2020","source":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32248729","citation_count":27,"is_preprint":false},{"pmid":"34233182","id":"PMC_34233182","title":"Regulation of NMDA receptor trafficking and gating by activity-dependent CaMKIIα phosphorylation of the GluN2A subunit.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/34233182","citation_count":27,"is_preprint":false},{"pmid":"32282091","id":"PMC_32282091","title":"Characterization of CaMKIIα holoenzyme stability.","date":"2020","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/32282091","citation_count":26,"is_preprint":false},{"pmid":"24469593","id":"PMC_24469593","title":"mTORC1 inhibition in the nucleus accumbens 'protects' against the expression of drug seeking and 'relapse' and is associated with reductions in GluA1 AMPAR and CAMKIIα levels.","date":"2014","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24469593","citation_count":26,"is_preprint":false},{"pmid":"28683307","id":"PMC_28683307","title":"Recruitment of Staufen2 Enhances Dendritic Localization of an Intron-Containing CaMKIIα mRNA.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28683307","citation_count":26,"is_preprint":false},{"pmid":"29137928","id":"PMC_29137928","title":"CaMKIIα expression in a mouse model of NMDAR hypofunction schizophrenia: Putative roles for IGF-1R and TLR4.","date":"2017","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/29137928","citation_count":26,"is_preprint":false},{"pmid":"30244246","id":"PMC_30244246","title":"Role of miR-148a in Mitigating Hepatic Ischemia-Reperfusion Injury by Repressing the TLR4 Signaling Pathway via Targeting CaMKIIα in Vivo and in Vitro.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30244246","citation_count":26,"is_preprint":false},{"pmid":"24787920","id":"PMC_24787920","title":"Apolipoprotein E4 impairs in vivo hippocampal long-term synaptic plasticity by reducing the phosphorylation of CaMKIIα and CREB.","date":"2014","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/24787920","citation_count":24,"is_preprint":false},{"pmid":"16616767","id":"PMC_16616767","title":"Opiate withdrawal induces dynamic expressions of AMPA receptors and its regulatory molecule CaMKIIalpha in hippocampal synapses.","date":"2006","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/16616767","citation_count":23,"is_preprint":false},{"pmid":"16023257","id":"PMC_16023257","title":"Retinal ganglion cell death and neuroprotection: Involvement of the CaMKIIalpha gene.","date":"2005","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/16023257","citation_count":22,"is_preprint":false},{"pmid":"26247621","id":"PMC_26247621","title":"CaMKIIα-GluA1 Activity Underlies Vulnerability to Adolescent Binge Alcohol Drinking.","date":"2015","source":"Alcoholism, clinical and experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/26247621","citation_count":22,"is_preprint":false},{"pmid":"24005308","id":"PMC_24005308","title":"Recombinant probes reveal dynamic localization of CaMKIIα within somata of cortical neurons.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/24005308","citation_count":22,"is_preprint":false},{"pmid":"33127463","id":"PMC_33127463","title":"The effects of lactobacilli (L. rhamnosus, L. reuteri, L. Plantarum) on LPS-induced memory impairment and changes in CaMKII-α and TNF-α genes expression in the hippocampus of rat.","date":"2020","source":"Physiology & behavior","url":"https://pubmed.ncbi.nlm.nih.gov/33127463","citation_count":21,"is_preprint":false},{"pmid":"27451410","id":"PMC_27451410","title":"Inhibition of CaMKIIα in the Central Nucleus of Amygdala Attenuates Fentanyl-Induced Hyperalgesia in Rats.","date":"2016","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/27451410","citation_count":21,"is_preprint":false},{"pmid":"33497737","id":"PMC_33497737","title":"Treadmill exercise enhances synaptic plasticity in the ischemic penumbra of MCAO mice by inducing the expression of Camk2a via CYFIP1 upregulation.","date":"2021","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33497737","citation_count":20,"is_preprint":false},{"pmid":"37365244","id":"PMC_37365244","title":"Adnp-mutant mice with cognitive inflexibility, CaMKIIα hyperactivity, and synaptic plasticity deficits.","date":"2023","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/37365244","citation_count":20,"is_preprint":false},{"pmid":"37153565","id":"PMC_37153565","title":"Tilianin improves cognition in a vascular dementia rodent model by targeting miR-193b-3p/CaM- and miR-152-3p/CaMKIIα-mediated inflammatory and apoptotic pathways.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37153565","citation_count":20,"is_preprint":false},{"pmid":"28730575","id":"PMC_28730575","title":"The Effect of Chronic Fluorosis on Calcium Ions and CaMKIIα, and c-fos Expression in the Rat Hippocampus.","date":"2017","source":"Biological trace element research","url":"https://pubmed.ncbi.nlm.nih.gov/28730575","citation_count":20,"is_preprint":false},{"pmid":"29107547","id":"PMC_29107547","title":"CaMKIIα Expression Defines Two Functionally Distinct Populations of Granule Cells Involved in Different Types of Odor Behavior.","date":"2017","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/29107547","citation_count":20,"is_preprint":false},{"pmid":"26174594","id":"PMC_26174594","title":"Opiate Exposure State Controls a D2-CaMKIIα-Dependent Memory Switch in the Amygdala-Prefrontal Cortical Circuit.","date":"2015","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26174594","citation_count":19,"is_preprint":false},{"pmid":"23041766","id":"PMC_23041766","title":"Effects of propofol on the activation of hippocampal CaMKIIα in depressed rats receiving electroconvulsive therapy.","date":"2012","source":"The journal of ECT","url":"https://pubmed.ncbi.nlm.nih.gov/23041766","citation_count":19,"is_preprint":false},{"pmid":"23695276","id":"PMC_23695276","title":"Large deletions encompassing the TCOF1 and CAMK2A genes are responsible for Treacher Collins syndrome with intellectual disability.","date":"2013","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/23695276","citation_count":18,"is_preprint":false},{"pmid":"24755854","id":"PMC_24755854","title":"CaMKIIα and caveolin-1 cooperate to drive ATP-induced membrane delivery of the P2X3 receptor.","date":"2014","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24755854","citation_count":18,"is_preprint":false},{"pmid":"28241801","id":"PMC_28241801","title":"The protective effects of propofol against CoCl2-induced HT22 cell hypoxia injury via PP2A/CAMKIIα/nNOS pathway.","date":"2017","source":"BMC anesthesiology","url":"https://pubmed.ncbi.nlm.nih.gov/28241801","citation_count":18,"is_preprint":false},{"pmid":"22768241","id":"PMC_22768241","title":"A role for dendritic translation of CaMKIIα mRNA in olfactory plasticity.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22768241","citation_count":17,"is_preprint":false},{"pmid":"29146590","id":"PMC_29146590","title":"CaMKIIα Mediates the Effect of IL-17 To Promote Ongoing Spontaneous and Evoked Pain in Multiple Sclerosis.","date":"2017","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29146590","citation_count":17,"is_preprint":false},{"pmid":"22993434","id":"PMC_22993434","title":"Activity-dependent modulation of the interaction between CaMKIIα and Abi1 and its involvement in spine maturation.","date":"2012","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/22993434","citation_count":17,"is_preprint":false},{"pmid":"32281712","id":"PMC_32281712","title":"Imperatorin ameliorates learning and memory deficits through BDNF/TrkB and ERK/CaMKIIα/CREB signaling in prenatally-stressed female offspring.","date":"2020","source":"Phytotherapy research : PTR","url":"https://pubmed.ncbi.nlm.nih.gov/32281712","citation_count":16,"is_preprint":false},{"pmid":"29352270","id":"PMC_29352270","title":"Non-canonical Wnt induces chondrocyte de-differentiation through Frizzled 6 and DVL-2/B-raf/CaMKIIα/syndecan 4 axis.","date":"2018","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/29352270","citation_count":16,"is_preprint":false},{"pmid":"31736725","id":"PMC_31736725","title":"Acute Chemogenetic Activation of CamKIIα-Positive Forebrain Excitatory Neurons Regulates Anxiety-Like Behaviour in Mice.","date":"2019","source":"Frontiers in behavioral neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31736725","citation_count":16,"is_preprint":false},{"pmid":"29151114","id":"PMC_29151114","title":"Non-canonical heterogeneous cellular distribution and co-localization of CaMKIIα and CaMKIIβ in the spinal superficial dorsal horn.","date":"2017","source":"Brain structure & function","url":"https://pubmed.ncbi.nlm.nih.gov/29151114","citation_count":16,"is_preprint":false},{"pmid":"38422650","id":"PMC_38422650","title":"Natural product Kaji-ichigoside F1 exhibits rapid antidepression via activating the AMPA-BDNF-mTOR pathway and inhibiting the NMDAR-CaMKIIα pathway.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38422650","citation_count":15,"is_preprint":false},{"pmid":"34667946","id":"PMC_34667946","title":"Characterization of six CaMKIIα variants found in patients with schizophrenia.","date":"2021","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/34667946","citation_count":15,"is_preprint":false},{"pmid":"25748600","id":"PMC_25748600","title":"L-type calcium channels contribute to 5-HT3-receptor-evoked CaMKIIα and ERK activation and induction of emesis in the least shrew (Cryptotis parva).","date":"2015","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/25748600","citation_count":15,"is_preprint":false},{"pmid":"18562151","id":"PMC_18562151","title":"Ethanol inhibition of recombinant NMDA receptors is not altered by coexpression of CaMKII-alpha or CaMKII-beta.","date":"2008","source":"Alcohol (Fayetteville, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/18562151","citation_count":15,"is_preprint":false},{"pmid":"31957543","id":"PMC_31957543","title":"Zika virus promotes CCN1 expression via the CaMKIIα-CREB pathway in astrocytes.","date":"2020","source":"Virulence","url":"https://pubmed.ncbi.nlm.nih.gov/31957543","citation_count":14,"is_preprint":false},{"pmid":"22582824","id":"PMC_22582824","title":"Bi-directional regulation of CaMKIIα phosphorylation at Thr286 by NMDA receptors in cultured cortical neurons.","date":"2012","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22582824","citation_count":14,"is_preprint":false},{"pmid":"31177064","id":"PMC_31177064","title":"Icariin ameliorates learning and memory impairments through ERK/CaMKIIα/CREB signaling and HPA axis in prenatally stressed female offspring.","date":"2019","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/31177064","citation_count":14,"is_preprint":false},{"pmid":"35305243","id":"PMC_35305243","title":"CaMKIIα Signaling Is Required for the Neuroprotective Effects of Dl-3-n-Butylphthalide in Alzheimer's Disease.","date":"2022","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/35305243","citation_count":14,"is_preprint":false},{"pmid":"28489932","id":"PMC_28489932","title":"CaMKIIα may modulate fentanyl-induced hyperalgesia via a CeLC-PAG-RVM-spinal cord descending facilitative pain pathway in rats.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28489932","citation_count":14,"is_preprint":false},{"pmid":"31750928","id":"PMC_31750928","title":"Regular Aerobic Exercise-Alleviated Dysregulation of CAMKIIα Carbonylation to Mitigate Parkinsonism via Homeostasis of Apoptosis With Autophagy.","date":"2020","source":"Journal of neuropathology and experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31750928","citation_count":13,"is_preprint":false},{"pmid":"26821292","id":"PMC_26821292","title":"CaMKIIα knockdown decreases anxiety in the open field and low serotonin-induced upregulation of GluA1 in the basolateral amygdala.","date":"2016","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/26821292","citation_count":13,"is_preprint":false},{"pmid":"33647396","id":"PMC_33647396","title":"Chemogenetic inhibition of ventral hippocampal CaMKIIα-expressing neurons attenuates anxiety- but not fear-like defensive behaviors in male Long-Evans hooded rats.","date":"2021","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/33647396","citation_count":13,"is_preprint":false},{"pmid":"26298628","id":"PMC_26298628","title":"Fragile X Syndrome FMRP Co-localizes with Regulatory Targets PSD-95, GABA Receptors, CaMKIIα, and mGluR5 at Fiber Cell Membranes in the Eye Lens.","date":"2015","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/26298628","citation_count":13,"is_preprint":false},{"pmid":"35287547","id":"PMC_35287547","title":"MicroRNA-3200-3p targeting CAMK2A modulates the proliferation and metastasis of glioma in vitro.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35287547","citation_count":12,"is_preprint":false},{"pmid":"25929186","id":"PMC_25929186","title":"Camk2a-Cre-mediated conditional deletion of chromatin remodeler Brg1 causes perinatal hydrocephalus.","date":"2015","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/25929186","citation_count":12,"is_preprint":false},{"pmid":"38828629","id":"PMC_38828629","title":"SIRT1 mediates the excitability of spinal CaMKIIα-positive neurons and participates in neuropathic pain by controlling Nav1.3.","date":"2024","source":"CNS neuroscience & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/38828629","citation_count":12,"is_preprint":false},{"pmid":"34532457","id":"PMC_34532457","title":"Effects of N-Methyl-D-aspartate receptor (NMDAR) and Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) on learning and memory impairment in depressed rats with different charge by modified electroconvulsive shock.","date":"2021","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34532457","citation_count":12,"is_preprint":false},{"pmid":"31736736","id":"PMC_31736736","title":"SK Channel Modulates Synaptic Plasticity by Tuning CaMKIIα/β Dynamics.","date":"2019","source":"Frontiers in synaptic neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/31736736","citation_count":12,"is_preprint":false},{"pmid":"37146745","id":"PMC_37146745","title":"Antidepressant effects of repeated s-ketamine administration as NMDAR Antagonist: Involvement of CaMKIIα and mTOR signaling in the hippocampus of CUMS mice.","date":"2023","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/37146745","citation_count":12,"is_preprint":false},{"pmid":"38936066","id":"PMC_38936066","title":"circADAMTS6 via stabilizing CAMK2A is involved in smoking-induced emphysema through driving M2 macrophage polarization.","date":"2024","source":"Environment international","url":"https://pubmed.ncbi.nlm.nih.gov/38936066","citation_count":11,"is_preprint":false},{"pmid":"37026450","id":"PMC_37026450","title":"The GHB analogue HOCPCA improves deficits in cognition and sensorimotor function after MCAO via CaMKIIα.","date":"2023","source":"Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/37026450","citation_count":11,"is_preprint":false},{"pmid":"30282777","id":"PMC_30282777","title":"Activated CaMKIIα Binds to the mGlu5 Metabotropic Glutamate Receptor and Modulates Calcium Mobilization.","date":"2018","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30282777","citation_count":11,"is_preprint":false},{"pmid":"36346645","id":"PMC_36346645","title":"Exploring the NCS-382 Scaffold for CaMKIIα Modulation: Synthesis, Biochemical Pharmacology, and Biophysical Characterization of Ph-HTBA as a Novel High-Affinity Brain-Penetrant Stabilizer of the CaMKIIα Hub Domain.","date":"2022","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36346645","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56666,"output_tokens":9039,"usd":0.152791,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19361,"output_tokens":8869,"usd":0.159265,"stage2_stop_reason":"end_turn"},"total_usd":0.312056,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"CaMKIIβ binds F-actin in dendritic spines and cell cortex while CaMKIIα is largely cytosolic; when co-expressed, the two isoforms form large heterooligomers, and a small fraction of CaMKIIβ is sufficient to dock the predominant CaMKIIα to the actin cytoskeleton, establishing CaMKIIβ as a targeting module for CaMKIIα localization.\",\n      \"method\": \"GFP-tagged CaMKII isoform live imaging, co-expression in neurons, F-actin co-localization assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct live-cell imaging with GFP-tagged proteins, multiple orthogonal localization methods, replicated across multiple expression conditions\",\n      \"pmids\": [\"9768845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Dendritic localization of CaMKIIα mRNA (via its 3'UTR signal) is required for normal postsynaptic density targeting of the protein; disrupting dendritic mRNA localization dramatically reduces CaMKIIα in PSDs and impairs late-phase LTP, spatial memory, fear conditioning, and object recognition memory.\",\n      \"method\": \"Knock-in mouse with mutated endogenous CaMKIIα 3'UTR, PSD fractionation, LTP electrophysiology, behavioral testing\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with multiple orthogonal readouts (biochemistry, electrophysiology, behavior), widely replicated concept\",\n      \"pmids\": [\"12408852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CaMKIIα enhances the desensitization of NR2B-containing NMDA receptors in an autophosphorylation-dependent manner; kinase-dead (K42R) and autophosphorylation-deficient (T286A) mutants fail to enhance desensitization, and Ca2+ chelation with BAPTA abrogates the effect. CaMKIIα decreases (rather than increases) desensitization of NR2A-containing receptors.\",\n      \"method\": \"Whole-cell patch-clamp electrophysiology in HEK293 cells co-expressing NMDA receptor subunits and CaMKIIα mutants, BAPTA loading\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution in heterologous cells with active-site and autophosphorylation-site mutagenesis, multiple mutant controls, single lab\",\n      \"pmids\": [\"15866054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NCAM clustering activates CaMKIIα via Ca2+ influx through associated voltage-dependent Ca2+ channels; activated CaMKIIα forms a complex with NCAM and RPTPα and phosphorylates RPTPα at Ser180/Ser204, increasing RPTPα phosphatase activity, which is required for NCAM-induced neurite outgrowth.\",\n      \"method\": \"Co-immunoprecipitation, serine phosphorylation assays, dominant-negative RPTPα mutants (S180A/S204A), neurite outgrowth assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, mutagenesis of phosphorylation sites, functional neurite outgrowth readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"18809727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CaMKIIα colocalizes with MUPP1 in the acrosomal region of spermatozoa and selectively binds PDZ domains 10–11 of MUPP1; Ca2+/calmodulin releases CaMKIIα from MUPP1, and competitive displacement of CaMKIIα from these PDZ domains (or CaMKII catalytic inhibition) triggers spontaneous acrosomal exocytosis, indicating CaMKIIα normally suppresses premature acrosomal secretion.\",\n      \"method\": \"Co-localization, in vitro binding assays mapping PDZ domain specificity, CaMKII inhibitor experiments, acrosomal exocytosis assays in mouse spermatozoa\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding domain mapping plus pharmacological inhibition with functional readout, single lab\",\n      \"pmids\": [\"19934217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CaMKIIα catalytic domains form paired (autoinhibited) and unpaired (active) conformations in living neurons; glutamate receptor activation triggers a structural transition from paired to unpaired conformation, consistent with a flip-flop switch model of persistent kinase activation.\",\n      \"method\": \"Fluorescence anisotropy and FRET imaging of Venus-tagged CaMKIIα in neurons, glutamate receptor stimulation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell FRET/anisotropy imaging with receptor stimulation, single lab, conformational model supported by structural prediction\",\n      \"pmids\": [\"19339497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CaMKIIα selectively translocates to inhibitory (GABAergic) synapses in response to moderate NMDAR activation that triggers GABAAR insertion; Thr286 autophosphorylation is necessary and sufficient to localize CaMKIIα at inhibitory synapses and enhance surface GABAAR expression. Stronger glutamatergic stimulation (coupled to AMPAR insertion) also causes Thr286 autophosphorylation but prevents accumulation at inhibitory synapses via calcineurin.\",\n      \"method\": \"Fluorescence imaging of CaMKIIα translocation in CA1 neurons, pharmacological NMDAR stimulation paradigms, phosphomimetic/phosphodeficient mutants, calcineurin inhibitor experiments, surface GABAAR quantification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (imaging, mutagenesis, pharmacology, receptor surface expression), mechanistically dissects stimulus-specific targeting\",\n      \"pmids\": [\"21059908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CaMKIIα interacts with Abi1 under resting conditions through the Abi1 tSNARE domain, which shares homology with the CaMKIIα regulatory domain; this interaction simultaneously inhibits CaMKIIα activity and Abi1-dependent Rac activation. Glutamate receptor activation dissociates the complex via calmodulin binding, and CaMKIIα phosphorylates Abi1 at Ser88 prior to dissociation, contributing to spine maturation.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assays, phosphorylation site mutagenesis, Rac activation assays, spine morphology analysis in rat hippocampal neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus kinase activity assay plus spine morphology, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"22993434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ΔFosB binds the CaMKIIα gene promoter in nucleus accumbens (NAc); chronic fluoxetine reduces ΔFosB binding at the CaMKIIα promoter by inducing histone H3 acetylation decreases and H3K9 dimethylation increases at that locus, suppressing CaMKIIα expression. CaMKII overexpression in NAc blocks fluoxetine's antidepressant effects, while CaMKII inhibition in NAc mimics fluoxetine.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), viral overexpression/inhibition in NAc, chronic social defeat stress paradigm\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with functional behavioral validation, single lab, two complementary genetic interventions\",\n      \"pmids\": [\"24240473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Inactive CaMKIIα constitutively binds the proximal intracellular C-terminal tail of mGluR5 in striatal neurons; Ca2+ activation of CaMKIIα causes its dissociation from mGluR5 and simultaneous recruitment to the adjacent GluN2B subunit of NMDARs, enabling CaMKIIα to phosphorylate GluN2B at a CaMKII-sensitive site.\",\n      \"method\": \"In vitro pulldown, co-immunoprecipitation in striatal neurons, Ca2+ manipulation, GluN2B phosphorylation assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus co-IP in neurons plus phosphorylation assay, single lab\",\n      \"pmids\": [\"24032403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In neuronal somata, CaMKIIα forms actin-dependent clusters (~1–4 µm) under basal conditions that disperse in a Ca2+-dependent manner within seconds of glutamate/glycine exposure and reform after washout; these clusters are distinct from the dendritic trafficking behavior of CaMKIIα.\",\n      \"method\": \"Novel recombinant probe (mRNA-display selected) labeling endogenous CaMKIIα in living rat cortical neurons, cytochalasin D actin disruption, Ca2+ imaging\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell imaging of endogenous protein with novel validated probe, pharmacological dissection, single lab\",\n      \"pmids\": [\"24005308\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IRBIT binds to CaMKIIα and suppresses its kinase activity by inhibiting calmodulin binding; IRBIT-deficient mice show elevated CaMKIIα-mediated phosphorylation of tyrosine hydroxylase (TH) in the ventral tegmental area, leading to increased catecholamine levels, hyperlocomotion, and social abnormalities.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase activity assays, calmodulin binding competition assays, IRBIT knockout mice, TH phosphorylation analysis in VTA\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with defined mechanism (calmodulin competition) + in vivo KO with substrate phosphorylation readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"25922519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"mTOR activity preserves the poly(A) tail length of CaMKIIα mRNA, preventing its deadenylation; the RNA-stabilizing protein HuD (via its poly(A)-binding third RRM domain) captures CaMKIIα mRNA and promotes its branch-specific dendritic expression, providing a molecular mechanism for synaptic tagging and capture.\",\n      \"method\": \"mTOR inhibition (rapamycin) in neurons, poly(A) tail assays, HuD overexpression/deletion mutants, dendritic CaMKIIα protein/mRNA quantification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (rapamycin, poly(A) assay, domain-deletion constructs), single lab\",\n      \"pmids\": [\"25944900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Elevated CaMKIIα protein in Fmr1 KO cortex causes hyperphosphorylation of long Homer proteins, disrupting mGluR5–Homer scaffolds at synapses; genetic or pharmacological inhibition of CaMKIIα restores mGluR5–Homer scaffolds and rescues circuit hyperexcitability/seizures in Fmr1 KO mice.\",\n      \"method\": \"CaMKIIα protein level quantification, Homer phosphorylation assays, CaMKIIα inhibitor (KN-93) and genetic inhibition, EEG/circuit excitability recordings in Fmr1 KO mice\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal interventions (pharmacological + genetic), biochemical substrate identification, functional circuit rescue, in vivo model\",\n      \"pmids\": [\"26670047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A de novo ASD-linked CaMKIIα E183V mutation in the catalytic domain reduces substrate phosphorylation and autophosphorylation, acts as a dominant-negative suppressor of wild-type CaMKIIα autophosphorylation, reduces binding to Shank3, L-type calcium channel subunits, and NMDAR subunits, and increases CaMKIIα turnover. Knock-in mice show reduced synaptic CaMKIIα, lower spine density, decreased excitatory synaptic transmission, hyperactivity, social deficits, and repetitive behaviors.\",\n      \"method\": \"In vitro kinase assays, co-immunoprecipitation, knock-in mouse model, subcellular fractionation, neuronal morphology analysis, electrophysiology, behavioral testing\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay + mutagenesis + co-IP + in vivo knock-in + electrophysiology + behavior, multiple orthogonal methods in one study\",\n      \"pmids\": [\"28130356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"De novo CAMK2A mutations identified in intellectual disability patients alter CaMKIIα auto-phosphorylation at Thr286 (either increasing or decreasing it), and all mutations affecting auto-phosphorylation also impair neuronal migration, establishing that tightly regulated Thr286 auto-phosphorylation is required for neuronal function and neurodevelopment.\",\n      \"method\": \"Whole-exome sequencing, biochemical autophosphorylation assays in patient-derived variants, neuronal migration assays\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical functional validation of multiple variants across multiple centers, direct functional (migration) readout, 24 individuals with 19 variants\",\n      \"pmids\": [\"29100089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"A splice-site CAMK2A variant in a neurodevelopmental disorder patient causes exon 11 skipping, deleting the regulatory segment responsible for CaMKII autoinhibition; missense variants predicted to disrupt kinase domain–regulatory segment interactions increase Thr286 phosphorylation in Neuro-2a cells, and a CaMKIIα mutant expressed in hippocampal neurons significantly increases A-type K+ currents, facilitating spike repolarization.\",\n      \"method\": \"Minigene splicing assay, structural modeling, immunoblotting in Neuro-2a cells, electrophysiology in primary hippocampal neurons\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional splicing assay + cellular phosphorylation assay + electrophysiology, single lab\",\n      \"pmids\": [\"29560374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The CAMK2A missense mutation p.His477Tyr (in the association/hub domain) is defective in self-oligomerization and unable to assemble into the multimeric holoenzyme; in vivo, it fails to rescue neuronal defects in C. elegans unc-43 mutants, and iPSC-derived neurons from the patient display profound synaptic defects.\",\n      \"method\": \"Biochemical self-oligomerization assay, C. elegans complementation (unc-43 ortholog), patient iPSC-derived neuron synaptic analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical domain function assay + in vivo ortholog complementation + human iPSC neurons, multiple orthogonal methods\",\n      \"pmids\": [\"29784083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Activated (Thr286-autophosphorylated) CaMKIIα directly binds the membrane-proximal C-terminal domain of mGlu5a via a tribasic KRR motif (K866-R-R868); mutation of this motif reduces co-immunoprecipitation of CaMKIIα with full-length mGlu5a, and CaMKIIα increases mGlu5a surface expression and modulates the kinetics of mGlu5a-mediated Ca2+ mobilization.\",\n      \"method\": \"In vitro pulldown with purified proteins, co-immunoprecipitation in heterologous cells, site-directed mutagenesis (KRR→AAA), cell-surface biotinylation, Ca2+ fluorimetry and single-cell Ca2+ imaging\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with purified proteins + mutagenesis + co-IP + functional Ca2+ assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"30282777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GHB analogs bind selectively to the CaMKIIα hub domain at a site revealed by a 2.2-Å X-ray crystal structure; binding promotes concentration-dependent increases in hub thermal stability and provides significant neuroprotection selectively under pathological CaMKIIα hyperactivation (excitotoxicity and cerebral ischemia), establishing the hub domain as a pharmacologically targetable site.\",\n      \"method\": \"Photoaffinity labeling, chemical proteomics, X-ray crystallography (2.2 Å), differential scanning fluorimetry (thermal stability), in vitro excitotoxicity assays, MCAO mouse model\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure + photoaffinity labeling + functional neuroprotection in vitro and in vivo, multiple orthogonal methods in one study\",\n      \"pmids\": [\"34330837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Under basal conditions CaMKIIα is recruited to the Shank3 subcompartment of the PSD via phase separation; Ca2+ rise induces GluN2B-mediated recruitment of active CaMKIIα forming CaMKIIα/GluN2B/PSD-95 condensates that autonomously disperse upon Ca2+ removal. Protein phosphatases control Ca2+-dependent shuttling of CaMKIIα between PSD nano-domains, and CaMKIIα activation further enlarges PSD assembly and induces structural LTP.\",\n      \"method\": \"Phase separation assays, live-cell imaging, FRAP, co-immunoprecipitation, phosphatase inhibitor experiments, structural LTP induction\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple imaging and biochemical methods for phase separation and condensate dynamics, single lab\",\n      \"pmids\": [\"33235361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Shank3 directly binds activated CaMKIIα between residues 829–1130 of Shank3; mutation of Shank3 residues 949RRK951 to alanines abolishes CaMKII binding in vitro and in cells. This CaMKII–Shank3 interaction, together with Shank3–LTCC interaction, is required for depolarization-induced CREB phosphorylation and c-Fos expression in hippocampal neurons (long-range plasma membrane–to–nucleus signaling).\",\n      \"method\": \"Co-immunoprecipitation from mouse forebrain, in vitro direct binding with purified proteins, alanine substitution mutagenesis, shRNA/rescue in hippocampal neurons, nuclear CREB phosphorylation and c-Fos assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro reconstitution + mutagenesis + co-IP from brain + shRNA/rescue with functional nuclear signaling readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32019829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CaMKIIα phosphorylates GluN2A at Ser1459 in response to synaptic activity mimicking LTP; Ser1459 phosphorylation promotes GluN2A interaction with the SNX27-retromer complex, enhancing endosomal recycling of GluN2A-NMDARs to the neuronal surface. Loss of CaMKIIα function blocks the glycine-induced increase in surface GluN2A-NMDARs.\",\n      \"method\": \"In vitro kinase assay, phosphorylation site mutagenesis, co-immunoprecipitation, SNX27 knockdown, surface NMDAR quantification, synaptic current recordings\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro phosphorylation + mutagenesis + co-IP + surface receptor trafficking assay + electrophysiology, independently replicated in companion paper (PMID:34233182)\",\n      \"pmids\": [\"32877683\", \"34233182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CaMKIIα holoenzyme stability is characterized by differential domain stability: the kinase domain alone is thermally unstable (Tm ~36°C), stabilized moderately by ATP/MgCl2 (Tm ~40°C) and markedly by the regulatory segment (Tm ~60°C); the hub domain alone is highly stable (Tm ~90°C); within the holoenzyme the kinase domain is stabilized and the hub domain is destabilized. A crystal structure of the kinase domain bound to p-coumaric acid reveals solvent-exposed hydrophobic residues in the substrate-binding pocket in the absence of regulatory segment.\",\n      \"method\": \"Differential scanning calorimetry (DSC), X-ray crystallography, mass photometry\",\n      \"journal\": \"Protein science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure + DSC + mass photometry in single study with multiple orthogonal biophysical methods\",\n      \"pmids\": [\"32282091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CaMKIIα phosphorylates the P2X3 receptor at Thr388 in the C-terminus; this phosphorylation increases P2X3 receptor binding to caveolin-1, and CaMKIIα cooperates with caveolin-1 to drive ATP-induced membrane insertion of P2X3 (and co-insertion of P2X2/P2X3) receptors, increasing surface P2X3 signaling.\",\n      \"method\": \"Mutagenesis of Thr388, in vitro kinase assay, co-immunoprecipitation, caveolin-1 knockdown, surface receptor trafficking assay in HEK293T cells and primary sensory neurons\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay + mutagenesis + co-IP + caveolin-1 KD + trafficking assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24755854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"S-nitrosation of CaMKIIα (at Cys280/Cys289) promotes its synaptosomal accumulation; GSNOR (S-nitrosoglutathione reductase) overexpression in neurons decreases CaMKIIα S-nitrosation and reduces CaMKIIα in synaptosomal fractions along with downstream p(S831)-GluR1, impairing LTP and cognition. Mutation of the S-nitrosation sites (C280/C289) recapitulates reduced synaptosomal accumulation.\",\n      \"method\": \"S-nitrosation site mutagenesis, synaptosomal fractionation, GSNOR transgenic/KO mice, LTP electrophysiology, behavioral testing\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site mutagenesis + fractionation + in vivo transgenic/KO models, single lab\",\n      \"pmids\": [\"28883020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Non-canonical Wnt-3a signals through Frizzled-6/DVL-2/syndecan-4 to recruit CaMKIIα to syndecan-4; CaMKIIα phosphorylates B-raf in vitro and in vivo, activating ERK1/2 signaling and driving chondrocyte de-differentiation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay demonstrating CaMKIIα phosphorylation of B-raf, siRNA knockdown, ERK1/2 activation assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay + co-IP + functional de-differentiation assay, single lab\",\n      \"pmids\": [\"29352270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CAMK2A phosphorylates EZH2 at T487 in a kinase-dependent manner, suppressing EZH2 methyltransferase activity and reducing H3K27me3 and EZH2 occupancy at the SOX2 locus, leading to epigenetic de-repression of SOX2 and support of tumor-initiating cell phenotypes in lung adenocarcinoma.\",\n      \"method\": \"Kinase-dependent phosphorylation assay, ChIP for H3K27me3 and EZH2, in vitro and in vivo tumor-initiating cell assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation assay + ChIP + functional rescue, single lab\",\n      \"pmids\": [\"32483123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PDSS1, via its catalytic product CoQ10 and elevation of intracellular calcium, induces CAMK2A phosphorylation (activation), which is required for STAT3 phosphorylation in the cytoplasm; phosphorylated STAT3 then translocates to the nucleus to promote oncogenic signaling and TNBC metastasis. A catalytically inactive PDSS1 mutant fails to activate CAMK2A.\",\n      \"method\": \"PDSS1 knockdown, catalytic mutant expression, CAMK2A phosphorylation assays, STAT3 phosphorylation/nuclear translocation assays, in vitro migration/invasion, in vivo metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant + knockdown + phosphorylation cascade assays, single lab\",\n      \"pmids\": [\"34408002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GluN2A Ser1459 phosphorylation by CaMKIIα (in response to glycine/LTP stimulation) promotes GluN2A-NMDAR interaction with the SNX27-retromer complex for endosomal recycling; the epilepsy-associated S1459G variant abolishes this interaction, reduces spine density, decreases excitatory transmission, and prolongs NMDAR-mediated synaptic current decay by increasing channel open duration.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, SNX27/CaMKIIα knockdown, surface NMDAR quantification, NMDAR single-channel and synaptic current recordings, spine density analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay + mutagenesis + co-IP + electrophysiology + trafficking assay, replicates and extends PMID:32877683 findings\",\n      \"pmids\": [\"34233182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Bi-directional regulation of CaMKIIα Thr286 autophosphorylation by NMDAR activation: low NMDA concentration (20 µM) up-regulates Thr286 phosphorylation via both NR2A and NR2B, while high concentration (100 µM) causes dephosphorylation via a phosphatase sensitive to high-concentration okadaic acid but not to PP2A or PP2B inhibitors specifically.\",\n      \"method\": \"Pharmacological NMDAR subunit inhibition and knockdown, NR2A/NR2B overexpression, phosphatase inhibitor profiling, immunoblotting of p-Thr286 in cortical neurons\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and molecular manipulation with multiple controls, single lab\",\n      \"pmids\": [\"22582824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CaMKIIα and CaMKIIβ co-expressed with NR1/NR2A or NR1/NR2B receptors do not alter the ethanol inhibition of NMDA receptor currents, and deletion of CaMKII binding domains in NR1 or NR2 or phospho-site mutations does not change ethanol sensitivity (negative result).\",\n      \"method\": \"Whole-cell patch-clamp in HEK293 cells co-expressing CaMKII isoforms and NMDAR subunits, GFP-tagged CaMKII, ethanol concentration-response\",\n      \"journal\": \"Alcohol\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct electrophysiology in reconstituted system with multiple mutant controls; negative finding well-controlled\",\n      \"pmids\": [\"18562151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The CaMKIIα hub domain contains a discrete small-molecule binding site; the novel ligand Ph-HTBA binds with mid-nanomolar affinity, induces a CaMKIIα Trp403 flip in the hub, markedly stabilizes the hub thermally, is brain-penetrant in mice (Kp,uu = 0.85), and selectively modulates the hub domain.\",\n      \"method\": \"Binding affinity assays, thermal shift assay, X-ray crystallography-informed structure-activity relationship, in vivo brain penetration (Kp,uu measurement)\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical binding + thermal stabilization + brain penetration in vivo, structural basis inferred from prior crystal structure, single lab\",\n      \"pmids\": [\"36346645\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CaMKIIα is a dodecameric (hub domain-assembled) Ca2+/calmodulin-activated Ser/Thr kinase that undergoes autophosphorylation at Thr286 to generate Ca2+-independent autonomous activity; it is targeted to excitatory or inhibitory postsynaptic sites depending on stimulus strength and calcineurin activity, is recruited to the PSD via phase separation involving Shank3 and GluN2B, and phosphorylates a wide array of synaptic substrates—including GluN2A (Ser1459, promoting NMDAR recycling), GluN2B, Homer proteins (disrupting mGluR5 scaffolds when CaMKIIα is elevated), RPTPα (Ser180/204, increasing phosphatase activity downstream of NCAM), B-raf (in non-canonical Wnt signaling), EZH2 (T487, suppressing its methyltransferase activity), and the P2X3 receptor (Thr388, driving membrane insertion)—while its local dendritic translation from dendritically localized mRNA (dependent on its 3'UTR and regulated by Staufen2, mTOR/HuD, and activity) is required for normal PSD delivery and synaptic/behavioral plasticity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CaMKII\\u03b1 is a Ca2+/calmodulin-activated Ser/Thr kinase that functions as a central transducer of synaptic activity, converting Ca2+ signals into persistent changes in synaptic strength and structure [#6, #15]. Its holoenzyme is built from a thermally stable, self-oligomerizing hub domain that assembles the multimeric enzyme and a kinase domain that is autoinhibited by a regulatory segment, with the kinase domain unstable in isolation but markedly stabilized by the regulatory segment within the holoenzyme [#17, #23]; in living neurons the catalytic domains transition from a paired (autoinhibited) to unpaired (active) conformation upon glutamate receptor activation, a flip-flop switch consistent with persistent activity [#5]. Thr286 autophosphorylation gates this autonomous activity and is bi-directionally tuned by NMDAR-driven Ca2+ and opposing phosphatases [#30], and tightly regulated Thr286 phosphorylation is required for neuronal migration and function [#15]. Activity recruits CaMKII\\u03b1 into the postsynaptic density through phase separation with Shank3 and Ca2+-dependent, GluN2B-mediated condensate formation with PSD-95, enabling structural LTP [#20, #21], and stimulus strength together with calcineurin directs CaMKII\\u03b1 to either excitatory or inhibitory synapses to control receptor surface expression [#6]. Once positioned, CaMKII\\u03b1 phosphorylates a broad substrate set to remodel synaptic signaling: GluN2A at Ser1459 to promote SNX27-retromer\\u2013dependent NMDAR recycling [#22, #29], GluN2B [#9], long Homer proteins to control mGluR5 scaffolds [#13], and RPTP\\u03b1 at Ser180/Ser204 downstream of NCAM to drive neurite outgrowth [#3]. Its function depends on dendritic localization of its own 3'UTR-bearing mRNA, whose stability and branch-specific translation are governed by mTOR and HuD; disrupting dendritic mRNA targeting depletes synaptic CaMKII\\u03b1 and impairs late-phase LTP and memory [#1, #12]. De novo CAMK2A mutations that alter catalytic activity, Thr286 autophosphorylation, regulatory-segment autoinhibition, or hub-domain oligomerization cause autism, intellectual disability, and neurodevelopmental disorders [#14, #15, #16, #17]. Beyond the nervous system, CaMKII\\u03b1 also acts in non-canonical Wnt signaling by phosphorylating B-raf [#26], in lung adenocarcinoma by phosphorylating EZH2 at T487 to de-repress SOX2 [#27], and in TNBC metastasis downstream of PDSS1/CoQ10 to drive STAT3 signaling [#28]. The hub domain is a pharmacologically targetable site bound by GHB analogs that confer neuroprotection under pathological hyperactivation [#19, #32].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established how the predominantly cytosolic CaMKII\\u03b1 is anchored at synaptic actin, showing that subcellular targeting is supplied in trans by the actin-binding CaMKII\\u03b2 isoform via hetero-oligomerization.\",\n      \"evidence\": \"GFP-tagged isoform live imaging and co-expression with F-actin co-localization in neurons\",\n      \"pmids\": [\"9768845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address how the holoenzyme is recruited specifically to the PSD\", \"Stoichiometry of \\u03b1/\\u03b2 in native holoenzymes not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated that dendritic mRNA localization, not just protein, is required for synaptic CaMKII\\u03b1 function, linking a 3'UTR-encoded RNA transport signal to PSD targeting, LTP and memory.\",\n      \"evidence\": \"Knock-in mouse with mutated endogenous 3'UTR, PSD fractionation, LTP electrophysiology, behavior\",\n      \"pmids\": [\"12408852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-binding factors mediating localization not identified here\", \"Local versus somatic translation contribution not separated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed CaMKII\\u03b1 has subunit-selective effects on NMDAR gating, decreasing NR2A but enhancing NR2B desensitization in an autophosphorylation- and Ca2+-dependent manner, distinguishing substrate-specific receptor regulation.\",\n      \"evidence\": \"Whole-cell patch-clamp in HEK293 with NMDAR subunits and K42R/T286A mutants, BAPTA loading\",\n      \"pmids\": [\"15866054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Heterologous system may not reflect native PSD context\", \"Phosphorylation sites mediating the effect not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified RPTP\\u03b1 as a CaMKII\\u03b1 substrate downstream of NCAM, defining a kinase-phosphatase relay in which CaMKII\\u03b1 phosphorylation increases RPTP\\u03b1 activity to drive neurite outgrowth.\",\n      \"evidence\": \"Reciprocal co-IP, Ser180/Ser204 phosphorylation assays, S180A/S204A mutants, neurite outgrowth\",\n      \"pmids\": [\"18809727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance for axon guidance not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved the conformational basis of persistent activation by directly imaging a paired-to-unpaired catalytic domain transition in neurons upon receptor stimulation.\",\n      \"evidence\": \"Fluorescence anisotropy and FRET imaging of Venus-tagged CaMKII\\u03b1 with glutamate stimulation\",\n      \"pmids\": [\"19339497\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Model relies on structural prediction; atomic confirmation not provided\", \"Relationship to Thr286 autophosphorylation not directly linked\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealed a non-neuronal autoinhibitory role in sperm: CaMKII\\u03b1 sequestered on MUPP1 PDZ domains suppresses premature acrosomal exocytosis until Ca2+/CaM releases it.\",\n      \"evidence\": \"Co-localization, PDZ domain binding mapping, CaMKII inhibition, acrosomal exocytosis assays in mouse sperm\",\n      \"pmids\": [\"19934217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct exocytosis substrate of CaMKII\\u03b1 not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established bi-directional control of Thr286 autophosphorylation by NMDAR signal strength, with low Ca2+ promoting and high Ca2+ triggering phosphatase-mediated dephosphorylation.\",\n      \"evidence\": \"Pharmacological NMDAR subunit manipulation, phosphatase inhibitor profiling, p-Thr286 immunoblotting in cortical neurons\",\n      \"pmids\": [\"22582824\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the high-OA-sensitive phosphatase not defined\", \"Mechanistic basis for concentration switch unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified Abi1 as a resting-state binding partner whose tSNARE domain mimics the CaMKII\\u03b1 regulatory segment, mutually inhibiting kinase and Rac signaling until Ca2+ dissociates the complex during spine maturation.\",\n      \"evidence\": \"Co-IP, kinase activity assays, Ser88 phospho-site mutagenesis, Rac assays, spine morphology in hippocampal neurons\",\n      \"pmids\": [\"22993434\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo role in spine maturation not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined an mGluR5\\u2192GluN2B switch in which Ca2+ activation releases CaMKII\\u03b1 from mGluR5 and recruits it to GluN2B for phosphorylation, coupling metabotropic and ionotropic receptor signaling.\",\n      \"evidence\": \"Pulldown, co-IP in striatal neurons, Ca2+ manipulation, GluN2B phosphorylation assay\",\n      \"pmids\": [\"24032403\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GluN2B phospho-site not mapped here\", \"Functional plasticity consequence not measured\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Characterized rapid, actin-dependent somatic clustering of endogenous CaMKII\\u03b1 that disperses with Ca2+, distinguishing somatic dynamics from dendritic trafficking.\",\n      \"evidence\": \"mRNA-display-selected recombinant probe imaging in living cortical neurons, cytochalasin D, Ca2+ imaging\",\n      \"pmids\": [\"24005308\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional purpose of somatic clusters unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked CaMKII\\u03b1 expression to mood-related circuitry, showing \\u0394FosB epigenetic control of the CaMKII\\u03b1 promoter in NAc determines antidepressant responses.\",\n      \"evidence\": \"ChIP, viral overexpression/inhibition in NAc, chronic social defeat stress\",\n      \"pmids\": [\"24240473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream NAc substrates of CaMKII not defined\", \"Causal histone marks not separated from \\u0394FosB binding\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended CaMKII\\u03b1 substrate range to the pain receptor P2X3, identifying Thr388 phosphorylation that promotes caveolin-1\\u2013dependent membrane insertion.\",\n      \"evidence\": \"Thr388 mutagenesis, in vitro kinase assay, co-IP, caveolin-1 knockdown, surface trafficking in HEK293T and sensory neurons\",\n      \"pmids\": [\"24755854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo nociceptive role not established here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified IRBIT as a calmodulin-competitive inhibitor of CaMKII\\u03b1, with loss causing excess TH phosphorylation and dopaminergic behavioral abnormalities, defining an endogenous brake on kinase activity.\",\n      \"evidence\": \"Co-IP, in vitro kinase and CaM-competition assays, IRBIT KO mice, TH phosphorylation in VTA\",\n      \"pmids\": [\"25922519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct TH phospho-site by CaMKII\\u03b1 not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the mTOR/HuD axis that stabilizes CaMKII\\u03b1 mRNA poly(A) tails and drives branch-specific dendritic expression, providing a molecular basis for synaptic tagging and capture.\",\n      \"evidence\": \"Rapamycin treatment, poly(A) tail assays, HuD domain-deletion mutants, dendritic mRNA/protein quantification\",\n      \"pmids\": [\"25944900\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link to in vivo plasticity not tested here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed that pathological elevation of CaMKII\\u03b1 hyperphosphorylates Homer to disrupt mGluR5 scaffolds, and that CaMKII\\u03b1 inhibition rescues Fragile X circuit hyperexcitability.\",\n      \"evidence\": \"Protein quantification, Homer phosphorylation, KN-93 and genetic inhibition, EEG in Fmr1 KO mice\",\n      \"pmids\": [\"26670047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Homer phospho-sites not mapped\", \"Whether elevated CaMKII\\u03b1 is cause or consequence in other disease contexts unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected CaMKII\\u03b1 to disease by showing the ASD-linked E183V catalytic mutation acts dominant-negatively, reduces partner binding, and produces synaptic and behavioral deficits in knock-in mice.\",\n      \"evidence\": \"In vitro kinase assays, co-IP, knock-in mouse, fractionation, morphology, electrophysiology, behavior\",\n      \"pmids\": [\"28130356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of accelerated turnover not defined\", \"Generalizability to other catalytic variants untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established CAMK2A as a neurodevelopmental disorder gene, showing that bidirectional dysregulation of Thr286 autophosphorylation impairs neuronal migration.\",\n      \"evidence\": \"Whole-exome sequencing, biochemical autophosphorylation assays of variants, neuronal migration assays\",\n      \"pmids\": [\"29100089\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate(s) controlling migration not identified\", \"Why both gain and loss of Thr286 phosphorylation are pathogenic not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a synaptic targeting function for CaMKII\\u03b1 Cys280/Cys289 S-nitrosation, which promotes synaptosomal accumulation and downstream GluR1 phosphorylation needed for LTP.\",\n      \"evidence\": \"S-nitrosation site mutagenesis, synaptosomal fractionation, GSNOR transgenic/KO mice, LTP, behavior\",\n      \"pmids\": [\"28883020\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural effect of nitrosation on holoenzyme not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked regulatory-segment integrity to disease, showing exon 11 skipping deletes the autoinhibitory segment and missense variants increase Thr286 phosphorylation and alter A-type K+ currents.\",\n      \"evidence\": \"Minigene splicing assay, structural modeling, Neuro-2a immunoblotting, hippocampal neuron electrophysiology\",\n      \"pmids\": [\"29560374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking hyperactive CaMKII\\u03b1 to K+ current change not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established the hub domain's essential oligomerization role by showing the His477Tyr variant cannot assemble the holoenzyme and fails to support neuronal function across worm and human iPSC models.\",\n      \"evidence\": \"Self-oligomerization assay, C. elegans unc-43 complementation, patient iPSC-derived neurons\",\n      \"pmids\": [\"29784083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative relationship between assembly defect and synaptic deficit not resolved\", \"Single variant\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped the structural basis of CaMKII\\u03b1\\u2013mGlu5 coupling, showing activated CaMKII\\u03b1 binds a tribasic KRR motif and increases mGlu5 surface expression and Ca2+ signaling kinetics.\",\n      \"evidence\": \"Pulldown with purified proteins, co-IP, KRR\\u2192AAA mutagenesis, surface biotinylation, Ca2+ imaging\",\n      \"pmids\": [\"30282777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo synaptic consequence not tested\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended CaMKII\\u03b1 to non-canonical Wnt signaling, identifying B-raf as a substrate that activates ERK1/2 to drive chondrocyte de-differentiation.\",\n      \"evidence\": \"Co-IP, in vitro B-raf phosphorylation, siRNA, ERK1/2 activation assays\",\n      \"pmids\": [\"29352270\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"B-raf phospho-site not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided biophysical architecture of the holoenzyme, quantifying domain-specific thermal stability and how the regulatory segment stabilizes the kinase while the hub is destabilized in context.\",\n      \"evidence\": \"Differential scanning calorimetry, X-ray crystallography, mass photometry\",\n      \"pmids\": [\"32282091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of reciprocal stabilization not tested in cells\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that CaMKII\\u03b1 is recruited to the PSD by phase separation with Shank3 and forms Ca2+-dependent GluN2B/PSD-95 condensates that drive structural LTP, with phosphatases controlling nano-domain shuttling.\",\n      \"evidence\": \"Phase separation assays, live imaging, FRAP, co-IP, phosphatase inhibitors, structural LTP\",\n      \"pmids\": [\"33235361\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo verification of condensates lacking\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mapped direct Shank3\\u2013CaMKII\\u03b1 binding (Shank3 949RRK951) and showed it enables depolarization-induced membrane-to-nucleus CREB/c-Fos signaling.\",\n      \"evidence\": \"Co-IP from forebrain, in vitro binding, alanine mutagenesis, shRNA/rescue, CREB phosphorylation and c-Fos assays\",\n      \"pmids\": [\"32019829\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism transmitting signal to nucleus not fully defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified GluN2A Ser1459 as a CaMKII\\u03b1 substrate that recruits the SNX27-retromer to recycle GluN2A-NMDARs to the surface during LTP, replicated and extended in a companion study including an epilepsy variant.\",\n      \"evidence\": \"In vitro kinase assay, phospho-site mutagenesis, co-IP, SNX27 knockdown, surface NMDAR quantification, electrophysiology\",\n      \"pmids\": [\"32877683\", \"34233182\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other retromer cargoes regulated by CaMKII\\u03b1 unknown\", \"In vivo memory consequence of S1459 phosphorylation not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a cancer kinase function: CaMKII\\u03b1 phosphorylates EZH2 at T487 to suppress its methyltransferase activity, de-repressing SOX2 and supporting tumor-initiating cells in lung adenocarcinoma.\",\n      \"evidence\": \"Phosphorylation assay, ChIP for H3K27me3/EZH2, tumor-initiating cell assays in vitro and in vivo\",\n      \"pmids\": [\"32483123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream activator of CaMKII\\u03b1 in tumors not defined here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed CaMKII\\u03b1 in a metabolic-oncogenic cascade, showing PDSS1/CoQ10-driven Ca2+ activates CaMKII\\u03b1 to phosphorylate STAT3 and promote TNBC metastasis.\",\n      \"evidence\": \"PDSS1 knockdown, catalytic mutant, CaMKII\\u03b1 and STAT3 phosphorylation assays, metastasis model\",\n      \"pmids\": [\"34408002\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct STAT3 phospho-site by CaMKII\\u03b1 not mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established the hub domain as a druggable allosteric site, solving a crystal structure of GHB-analog binding that thermally stabilizes the hub and confers neuroprotection selectively under hyperactivation.\",\n      \"evidence\": \"Photoaffinity labeling, chemical proteomics, 2.2-\\u00c5 X-ray structure, DSF, excitotoxicity and MCAO models\",\n      \"pmids\": [\"34330837\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking hub stabilization to reduced pathological activity not fully defined\", \"Selectivity over other CaMKII isoforms not detailed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Advanced hub-domain pharmacology with a brain-penetrant ligand (Ph-HTBA) that binds at mid-nanomolar affinity and induces a Trp403 conformational flip, validating the hub as a tractable CNS target.\",\n      \"evidence\": \"Binding affinity, thermal shift, SAR informed by crystallography, in vivo brain penetration (Kp,uu)\",\n      \"pmids\": [\"36346645\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Therapeutic efficacy in disease models not shown here\", \"Functional kinase consequence of Trp403 flip not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse substrate phosphorylation events, condensate dynamics, and bidirectional Thr286 regulation are integrated to encode specific synaptic and behavioral plasticity outcomes in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified in vivo map linking individual substrate phosphorylations to plasticity readouts\", \"Mechanism distinguishing physiological vs pathological hyperactivation incompletely defined\", \"Substrate selectivity rules for the activated holoenzyme not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 9, 13, 22, 24, 26, 27, 29]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [3, 15, 22, 24, 27]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 11, 7]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 18, 24]},\n      {\"term_id\": \"GO:0014069\", \"supporting_discovery_ids\": [1, 20, 21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 6, 20, 22, 29]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 18, 26, 28]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 14, 15, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [13, 14, 15, 27, 28, 29]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"complexes\": [\n      \"CaMKII holoenzyme (dodecameric hub-assembled)\",\n      \"CaMKII\\u03b1/GluN2B/PSD-95 condensate\",\n      \"NCAM/RPTP\\u03b1/CaMKII\\u03b1 complex\"\n    ],\n    \"partners\": [\n      \"SHANK3\",\n      \"GRIN2B\",\n      \"GRM5\",\n      \"PTPRA\",\n      \"MPDZ\",\n      \"ABI1\",\n      \"DLG4\",\n      \"EZH2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}