Affinage

ADCY8

Adenylate cyclase type 8 · UniProt P40145

Round 2 corrected
Length
1251 aa
Mass
140.1 kDa
Annotated
2026-04-28
80 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ADCY8 is a Ca²⁺/calmodulin-stimulated transmembrane adenylyl cyclase that converts ATP to cAMP preferentially in response to store-operated Ca²⁺ entry, functioning as a critical node coupling calcium dynamics to compartmentalized cAMP signaling in neurons, cardiomyocytes, pancreatic beta cells, and adipocytes. Ca²⁺/calmodulin activates ADCY8 through a disinhibitory mechanism at a C-terminal IQ-like motif, while the N-terminus directly binds Orai1 to form a microdomain linking store-operated Ca²⁺ entry to cAMP production, and also recruits PP2A in a Ca²⁺/calmodulin-competitive manner; an AKAP79/150-anchored PKA complex phosphorylates Ser-112 to provide negative feedback on cAMP output (PMID:10075700, PMID:22494970, PMID:16258073, PMID:22976297). ADCY8 is required for GLP-1 receptor-mediated cAMP generation and insulin secretion in beta cells, for recovery from presynaptic silencing in hippocampal neurons, for SDF1/cAMP-dependent retinal axon midline crossing, and for cAMP-PKA-mediated lipolysis in adipose tissue (PMID:21046358, PMID:18480272, PMID:20505109, PMID:40527393). The 3.5 Å cryo-EM structure of AC8 bound to Gαs and Ca²⁺/calmodulin reveals the ordered domain architecture and regulatory contact sites, while chronic cardiac overexpression engages metabolic reprogramming and a calcium/PKA/RelA-NF-κB inflammatory axis (PMID:38351373, PMID:36515265, PMID:38499959).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1994 High

    Cloning of ADCY8 from rat brain established it as a novel Ca²⁺/calmodulin-stimulated adenylyl cyclase with synergistic Gαs activation and predominant hippocampal/cortical expression, defining the founding biochemical identity of the enzyme.

    Evidence cDNA cloning with heterologous expression in HEK293 cells, enzymatic activity assays, in situ hybridization

    PMID:8163524

    Open questions at the time
    • Structural basis of CaM stimulation unknown
    • In vivo function not addressed
    • No information on post-translational regulation
  2. 1999 High

    Identification of two calmodulin-binding sites (N-terminal Ca²⁺-dependent and C-terminal IQ-like) and demonstration that Ca²⁺/calmodulin activates ADCY8 through a disinhibitory mechanism at the C-terminal site resolved the long-standing question of how calcium stimulation is transduced.

    Evidence Overlay assays, site-directed mutagenesis, synthetic peptide studies, and functional activity assays

    PMID:10075700

    Open questions at the time
    • Structural visualization of CaM-AC8 interaction not achieved
    • Relative contribution of each CaM lobe unresolved
    • In vivo relevance of disinhibition model untested
  3. 2002 High

    Cardiac-specific transgenic overexpression revealed that ADCY8-generated cAMP enhances SR Ca²⁺ uptake and contractility without affecting L-type Ca²⁺ channels, establishing that cAMP produced by ADCY8 is functionally compartmentalized in cardiomyocytes.

    Evidence Transgenic mouse model with Langendorff perfusion, patch-clamp, and fluorescent Ca²⁺ imaging

    PMID:12206999

    Open questions at the time
    • Molecular basis of cAMP compartmentation not identified
    • Role of endogenous cardiac ADCY8 vs overexpression artifacts unclear
  4. 2003 High

    The discovery that cardiac ADCY8 overexpression selectively remodels PDE isoform activity (upregulating PDE4/PDE1 for cAMP while decreasing PDE1/PDE2 for cGMP) explained the mechanism shielding L-type Ca²⁺ channels from cAMP elevation.

    Evidence PDE activity assays, pharmacological stimulation, and electrophysiology in transgenic mice

    PMID:12890691

    Open questions at the time
    • Whether PDE remodeling is a direct ADCY8 effect or secondary adaptation unknown
    • Physiological relevance under non-overexpression conditions untested
  5. 2005 High

    Identification of PP2A as a direct N-terminal binding partner of ADCY8, with Ca²⁺/calmodulin competitively displacing PP2A, revealed a regulatory switch connecting phosphatase and cyclase activities at the same signaling microdomain in lipid rafts.

    Evidence Yeast two-hybrid, GST pulldown, PP2A enzymatic activity assays, lipid raft co-fractionation in HEK293 and mouse forebrain

    PMID:16258073

    Open questions at the time
    • Physiological substrates of ADCY8-associated PP2A unknown
    • Whether PP2A modulates ADCY8 catalytic activity directly not tested
  6. 2008 High

    Genetic dissection using single and double knockout mice demonstrated a specific, non-redundant role for ADCY8 (but not AC1) in recovery from depolarization-induced presynaptic silencing, establishing its unique contribution to activity-dependent synaptic resetting.

    Evidence AC1⁻/⁻, AC8⁻/⁻, and double-KO neurons with presynaptic silencing assays and cAMP pharmacology

    PMID:18480272

    Open questions at the time
    • Downstream cAMP targets mediating recovery unidentified
    • Brain region and circuit specificity of this role not mapped
  7. 2008 High

    Real-time FRET-based cAMP imaging demonstrated that ADCY8 is preferentially activated by capacitative Ca²⁺ entry over other Ca²⁺ sources, with differential calmodulin N- and C-lobe dependence distinguishing it from AC1, establishing the Ca²⁺ entry mode selectivity concept.

    Evidence FRET cAMP sensors, Ca²⁺ entry mode pharmacology, calmodulin lobe mutagenesis

    PMID:19029295

    Open questions at the time
    • Physical basis for preferential coupling to CCE not yet identified
    • Whether lobe selectivity applies in native neurons untested
  8. 2009 High

    The finding that Orai1/STIM1-mediated store-operated Ca²⁺ entry (but not TRPC channels) specifically activates ADCY8, with all three proteins co-distributing in lipid rafts, identified the molecular components of the CCE-cAMP microdomain.

    Evidence Co-expression, adenylyl cyclase assays, Ca²⁺ entry pharmacology, co-localization imaging, and raft fractionation in HEK293 cells

    PMID:19171672

    Open questions at the time
    • Direct protein-protein interaction between AC8 and Orai1 not yet demonstrated
    • Native tissue validation limited
  9. 2010 High

    Three advances established ADCY8's non-redundant physiological roles: AKAP79/150 was shown to scaffold AC8 and limit its Ca²⁺ sensitivity in pancreatic beta cells and neurons; ADCY8 knockdown blocked GLP-1-mediated cAMP, Ca²⁺ signaling, and insulin exocytosis (with glucotoxicity downregulating ADCY8 as a disease-relevant mechanism); and morpholino knockdown in zebrafish proved ADCY8 is required cell-autonomously for SDF1/cAMP-mediated retinal axon midline crossing.

    Evidence Co-IP and live-cell cAMP imaging with endogenous validation (AKAP79); siRNA/adenoviral rescue in INS-1E cells, rat and human islets (GLP-1); morpholino knockdown with cell-autonomous rescue in zebrafish (axon guidance)

    PMID:20410303 PMID:20505109 PMID:21046358

    Open questions at the time
    • AKAP79 binding site on AC8 not mapped
    • Which AC8 domains mediate GLP-1R coupling unknown
    • Mammalian validation of axon guidance role lacking
  10. 2012 High

    Demonstration that the ADCY8 N-terminus directly binds Orai1's N-terminus, coordinating local Ca²⁺ and cAMP signals, and that AKAP79-recruited PKA phosphorylates Ser-112 as a negative feedback mechanism, completed the core regulatory circuit of the AC8 signaling microdomain.

    Evidence Pulldown/co-IP, FRET biosensors targeted to AC8/Orai1 microdomains (Orai1 binding); S112A mutagenesis with real-time cAMP imaging during Ca²⁺ oscillations (PKA feedback)

    PMID:22494970 PMID:22976297

    Open questions at the time
    • Structural basis of AC8-Orai1 interaction unresolved
    • Additional phosphorylation sites on AC8 not surveyed
    • Whether Ser-112 phosphorylation occurs in vivo not shown
  11. 2019 Medium

    The role of complex N-glycosylation and cytoskeletal association in targeting ADCY8 to caveolin-1-containing lipid rafts explained how ADCY8 achieves its specific plasma membrane microdomain localization required for signaling fidelity.

    Evidence Live-cell imaging, biochemical fractionation, mutagenesis of glycosylation sites, caveolin-1 co-IP

    PMID:30746562

    Open questions at the time
    • Specific glycosylation sites critical for raft targeting not fully mapped
    • Single-lab study without independent replication
    • In vivo consequences of mislocalization untested
  12. 2022 High

    Comprehensive multi-omic profiling of cardiac ADCY8-overexpressing mice revealed system-level metabolic adaptation — a shift from fatty acid oxidation to aerobic glycolysis with enhanced pentose phosphate shunt activity, upregulated proteasome/autophagy, and maintained ATP homeostasis — explaining how the heart tolerates chronic cAMP elevation without hypertrophy.

    Evidence Transgenic TGAC8 mouse model with transcriptomics, proteomics, metabolic flux analysis, echocardiography

    PMID:36515265

    Open questions at the time
    • Causal hierarchy among metabolic adaptations not established
    • Whether adaptations are reversible upon ADCY8 normalization unknown
  13. 2024 High

    The 3.5 Å cryo-EM structure of AC8 bound to Gαs and Ca²⁺/calmodulin provided the first high-resolution view of a Ca²⁺-stimulated adenylyl cyclase, revealing ordered domain architecture, Gαs and CaM contact sites, and a negatively charged extracellular pocket of unknown function, while the captured state unexpectedly disfavored tight nucleotide binding.

    Evidence Cryo-EM at 3.5 Å, LiP-MS, and crosslinking mass spectrometry of bovine AC8

    PMID:38351373

    Open questions at the time
    • Active catalytic conformation with bound substrate not captured
    • CaM-induced conformational changes not fully resolved
    • Functional significance of extracellular pocket unknown
  14. 2024 Medium

    Discovery that chronic ADCY8-driven cAMP activates a cell-autonomous calcium/PKA/RelA-NF-κB inflammatory axis in cardiomyocytes, triggering non-cell-autonomous immune cell expansion and systemic inflammation preceding fibrosis, linked AC8 activity to inflammatory pathology.

    Evidence TGAC8 mice with NF-κB/RelA analysis, PKA inhibition, flow cytometry, ELISA, cardiac histology

    PMID:38499959

    Open questions at the time
    • Whether endogenous AC8 levels can drive this axis unknown
    • Single-lab study
    • Specific PKA substrates upstream of RelA not identified
  15. 2025 Medium

    Two studies extended ADCY8's metabolic roles: CRISPR deletion in glioma cells reversed the Warburg effect by shifting metabolism toward oxidative phosphorylation, while Adcy8⁻/⁻ mice showed impaired adipose lipolysis with loss of forskolin-responsive cAMP-PKA signaling, establishing ADCY8 as a required component of lipolytic cAMP generation in vivo.

    Evidence CRISPR-KO in U87MG with proteomics and metabolic flux analysis (glioma); Adcy8⁻/⁻ mice on normal and high-fat diets with cAMP/PKA substrate assays (adipose)

    PMID:40527393 PMID:40669556

    Open questions at the time
    • Whether AC8's metabolic role in glioma is generalizable across tumor types untested
    • Adipose tissue phenotype not yet linked to specific AC8-interacting proteins
    • Both are single-lab findings requiring replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: the structural basis of the AC8-Orai1 interaction and how it is regulated, whether Ser-112 phosphorylation feedback operates in vivo, the identity of the extracellular pocket ligand revealed by cryo-EM, and whether endogenous cardiac AC8 levels can drive the NF-κB inflammatory axis observed in overexpression models.
  • No AC8-Orai1 co-structure exists
  • In vivo Ser-112 phosphorylation not confirmed
  • Extracellular pocket function unknown
  • Endogenous cardiac AC8 contribution to inflammation not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0009975 cyclase activity 5 GO:0016740 transferase activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1430728 Metabolism 3 R-HSA-112316 Neuronal System 2 R-HSA-168256 Immune System 1
Partners
AKAP5CALM1CAV1GNASORAI1PPP2CAPPP2R1ASTIM1
Complex memberships
AC8-AKAP79/150-PKA signaling complexAC8-Orai1-STIM1 store-operated Ca²⁺ entry microdomainAC8-PP2A core dimer complex

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 ADCY8 (type VIII adenylyl cyclase) was cloned from rat brain and characterized as a 1248-amino acid, dual-transmembrane-span protein that is stimulated up to 40-fold by Ca²⁺/calmodulin (EC50 ~53 nM calmodulin) and shows synergistic activation by Gαs. It is expressed most abundantly in dentate gyrus granule cells, hippocampal CA1–CA3 pyramidal cells, entorhinal and piriform cortices, and produces a novel 165-kDa glycoprotein in heterologous cells. cDNA cloning, stable expression in HEK293 cells, adenylyl cyclase activity assays, in situ hybridization, Western blot The Journal of biological chemistry High 8163524
1999 Two calmodulin-binding sites were identified in ADCY8: an N-terminal Ca²⁺-dependent site (typical amphipathic helix motif) and a C-terminal IQ-like site. Mutagenesis showed the C-terminal site is primarily responsible for Ca²⁺/calmodulin stimulation, and its removal produces a hyperactivated, Ca²⁺-insensitive enzyme, suggesting Ca²⁺/calmodulin activates ADCY8 via a disinhibitory mechanism. Overlay assays, site-directed mutagenesis, synthetic peptide studies, functional adenylyl cyclase activity assays The Journal of biological chemistry High 10075700
2002 Cardiac-specific transgenic expression of human ADCY8 in mice increased left ventricular systolic pressure ~2-fold, accelerated heart rate by 40%, increased Ca²⁺ transients by 30%, and accelerated relaxation, without altering L-type Ca²⁺ current amplitude. This demonstrated that ADCY8-generated cAMP specifically activates sarcoplasmic reticulum Ca²⁺ uptake but not sarcolemmal Ca²⁺ influx, revealing strong compartmentation of the cAMP signal. Transgenic mouse model, Langendorff heart perfusion, patch-clamp electrophysiology, fluorescent Ca²⁺ imaging (fluo-3 AM), isolated cardiomyocyte contractility measurements FASEB journal High 12206999
2003 Cardiac ADCY8 overexpression in transgenic mice upregulated cAMP-phosphodiesterase (PDE) activity, specifically increasing PDE4 and PDE1 hydrolytic activity toward cAMP, while decreasing PDE1/PDE2 activity toward cGMP. This PDE isoform rearrangement created cAMP compartmentation that shielded L-type Ca²⁺ channels from elevated cAMP and protected cardiomyocytes from Ca²⁺ overload. Muscarinic agonist carbachol inhibited contractility in AC8TG but not NTG mice. Transgenic mouse model, PDE activity assays, pharmacological stimulation (isoprenaline, IBMX, carbachol), patch-clamp electrophysiology FASEB journal High 12890691
2005 The N-terminus of ADCY8 directly interacts with the catalytic subunit of protein phosphatase 2A (PP2A_C) and the scaffolding subunit PP2A_A (forming a PP2A core dimer complex). PP2A_C pulled down from HEK293 and mouse forebrain membranes was catalytically active. Ca²⁺/calmodulin binding to the ADCY8 N-terminus antagonized PP2A_C association, revealing competitive regulation. Both PP2A_C and ADCY8 co-localize in lipid rafts. Yeast two-hybrid screen, GST pulldown with affinity precipitation, enzymatic PP2A activity assays, lipid raft fractionation Molecular pharmacology High 16258073
2005 ADCY8 expression in mouse brain begins embryonically (E12), initially restricted to epithalamus, hypothalamus, superior colliculus, and spinal cord. Expression broadens and increases postnatally, particularly in thalamus and cerebral cortex, with a transient peak in somatosensory cortex layer IV. This complementary pattern to AC1 (which is more broadly expressed embryonically) implies distinct developmental roles in Ca²⁺/activity-modulated cAMP signaling. In situ hybridization across embryonic and postnatal mouse brain stages The Journal of comparative neurology Medium 15844169
2008 AC8 (but not AC1) plays a critical role in recovery of synaptic function after depolarization-induced presynaptic silencing. In neurons from AC1/AC8 double-knockout mice, recovery from adaptive silencing was strongly inhibited; this phenotype was fully reproduced in AC8-deficient but not AC1-deficient cells, demonstrating a specific, non-redundant role for ADCY8 in resetting the balance of active versus silent synapses after strong activity. Genetic knockout mice (AC1-/-, AC8-/-, double KO), presynaptic silencing assay, cAMP pathway pharmacology (forskolin), synaptic activity measurement The Journal of neuroscience High 18480272
2008 AC1 and AC8, despite both being Ca²⁺/calmodulin-stimulated, show distinct regulatory mechanisms: AC8 is more dependent on capacitative Ca²⁺ entry (CCE) than AC1. Real-time FRET-based cAMP imaging showed that the two ACs respond differently to dynamic Ca²⁺ events, with differences arising from their distinct modes of calmodulin interaction and the differential roles of the N- and C-lobes of calmodulin. In vivo and in vitro adenylyl cyclase activity assays, FRET-based real-time cAMP imaging, Ca²⁺ entry mode pharmacology, calmodulin lobe mutagenesis The Journal of biological chemistry High 19029295
2009 Capacitative Ca²⁺ entry (CCE) mediated specifically by Orai1 and STIM1 (but not TRPC channels or arachidonate-activated channels) robustly activates ADCY8. ADCY8, Orai1, and STIM1 co-localize at the plasma membrane and all three proteins co-distribute in lipid rafts, forming a CCE-cAMP microdomain. Co-expression of Orai1/STIM1 in HEK293 cells, adenylyl cyclase activity assays, Ca²⁺ entry pharmacology, co-localization imaging, lipid raft fractionation Molecular pharmacology High 19171672
2009 Adcy8 is differentially expressed in specific brain regions of mouse strains differing in avoidance behavior, and the ADCY8 locus maps to a QTL for avoidance behavior on mouse chromosome 15 syntenic with human 8q24 (linked to bipolar disorder). Chronic carbamazepine (acting via adenylyl cyclase activity) significantly reduced mouse avoidance behavior, providing a functional link between ADCY8 and mood-related behavior. Chromosome substitution strain QTL mapping, behavioral phenotyping (automated home-cage registration), brain regional expression analysis, pharmacological intervention (carbamazepine infusion) Biological psychiatry Medium 19691954
2010 AKAP79/150 directly associates with Ca²⁺-stimulable ADCY8 and limits ADCY8 sensitivity to intracellular Ca²⁺ events. This functional interaction was demonstrated in HEK293 cells overexpressing both proteins and confirmed endogenously in pancreatic insulin-secreting cells and hippocampal neurons. Co-immunoprecipitation, high-resolution live-cell cAMP imaging, endogenous expression validation in pancreatic and neuronal cells The Journal of biological chemistry High 20410303
2010 ADCY8 is required cell-autonomously in zebrafish retinal neurons for normal midline crossing. Knockdown of ADCY8 made retinal axons insensitive to the chemokine SDF1 (which normally activates cAMP signaling to antagonize slit-mediated repulsion) and induced ipsilateral misprojections. This established ADCY8 as an essential component of a signaling pathway opposing midline repellent guidance cues before axons reach their targets. Morpholino knockdown in zebrafish, in vivo retinal axon tracing, genetic epistasis with slit signaling pathway, cell-autonomous rescue experiments The Journal of neuroscience High 20505109
2010 ADCY8 is central to GLP-1 receptor signaling in pancreatic beta cells. Knockdown of ADCY8 blocked GLP-1-induced cAMP generation, Ca²⁺ signaling, CRE activation, and amplification of exocytosis. Chronic high glucose (glucotoxicity) markedly downregulated ADCY8 expression in INS-1E cells and rat/human islets, and re-expression of ADCY8 (but not GLP-1R) recovered GLP-1 signaling under glucotoxic conditions. siRNA knockdown, adenoviral re-expression, cAMP measurement, Ca²⁺ imaging, CRE reporter assay, membrane capacitance measurement of exocytosis, transcriptomic analysis, quantitative PCR in rat and human islets Diabetologia High 21046358
2012 ADCY8 directly binds the N-terminus of Orai1 (the SOC channel pore component) via its own amino terminus. This protein-protein interaction coordinates subcellular changes in both Ca²⁺ and cAMP at the AC8/Orai1 microdomain. High-resolution targeted biosensors showed that the direct interaction is responsible for crosstalk between the two signaling pathways, with Orai1 functioning as an integral component of the signaling complex. Protein-protein interaction assays (pulldown/co-IP), high-resolution FRET-based biosensors targeted to AC8 and Orai1 microdomains, pharmacological and genetic disruption of interaction Science signaling High 22494970
2012 AKAP79-recruited PKA phosphorylates ADCY8 at Ser-112 within the N-terminus (near the AKAP79 association site), providing a novel negative feedback mechanism. PKA-mediated phosphorylation reduced the on-rate of cAMP production during Ca²⁺ oscillations in wild-type but not non-phosphorylatable (S112A) ADCY8 mutants. This action of PKA was not mediated indirectly through PP2A B56δ subunits. Site-directed mutagenesis (S112A), FRET-based real-time cAMP imaging during Ca²⁺ oscillations, pharmacological PKA manipulation, co-immunoprecipitation Journal of cell science High 22976297
2012 Interleukin-1β (IL-1β) induces de novo expression of ADCY8 in vascular smooth muscle cells (VSMCs) during trans-differentiation to an inflammatory/migratory phenotype. The Notch pathway (via transcriptional targets Hrt1 and Hrt3) attenuates this IL-1β-mediated ADCY8 upregulation. In a rat carotid balloon-injury model of restenosis, de novo ADCY8 expression coincided with Notch3 pathway downregulation in vivo. Pharmacological Notch inhibition and activation in VSMCs, overexpression of Hrt1/Hrt3, IL-1β stimulation assays, in vivo rat carotid balloon-injury model with expression analysis The Journal of biological chemistry Medium 22613711
2019 AC8 enriches in lipid raft microdomains via complex N-glycosylation and cytoskeletal association during trafficking to the plasma membrane. Live-cell imaging and biochemical approaches revealed a dynamic interaction between AC8 and caveolin-1 that affects AC8 processing, targeting, and responsiveness. Site-directed mutagenesis and pharmacological approaches showed that N-glycosylation is required for proper lipid raft targeting. Live-cell imaging, biochemical fractionation, site-directed mutagenesis, pharmacological disruption of cytoskeleton and glycosylation, co-immunoprecipitation with caveolin-1 The Journal of membrane biology Medium 30746562
2021 AC8 plays a relevant role in breast cancer cells supporting proliferation and migration. Breast cancer cells overexpress AC8, which shifts the AC8-Orai1α stoichiometry in favor of AC8, leading to impairment of PKA-dependent Orai1α inactivation (phosphorylation at serine-34) and enhanced store-operated Ca²⁺ entry (SOCE), thereby contributing to enhanced cancer hallmarks. AC8 overexpression/knockdown in breast cancer cells, Orai1α phosphorylation assays, SOCE measurement, proliferation and migration assays Cells Medium 34070268
2022 Marked cardiac-specific overexpression of ADCY8 (TGAC8 mice) drives sustained increases in heart rate, ejection fraction, and cardiac output without classical hypertrophy. Adaptation involves: increased protein synthesis, proteasome activity, and autophagy; elevated Nrf-2, Hsp90α, and ACC2 protein levels; a metabolic shift from fatty acid oxidation to aerobic glycolysis with increased pentose phosphate shunt activity; and maintenance of normal LV ATP and phosphocreatine levels despite increased energy demand. Omics identified >2,000 transcripts/proteins differing between TGAC8 and WT. Cardiac-specific transgenic mouse model, unbiased transcriptomics and proteomics, metabolic flux analysis, histology, echocardiography eLife High 36515265
2024 Cryo-EM structure of bovine AC8 bound to stimulatory Gαs and Ca²⁺/calmodulin was determined at 3.5 Å resolution, revealing the architecture of ordered AC8 domains bound to Gαs and forskolin. Limited proteolysis and crosslinking mass spectrometry (LiP-MS and XL-MS) identified contact sites between AC8 and its regulators CaM, Gαs, and Gβγ, and inferred conformational changes induced by these interactions. The captured state does not favor tight nucleotide binding despite well-resolved forskolin density. The extracellular surface features a negatively charged pocket as a potential site for unknown interactors. Cryo-EM (3.5 Å resolution), limited proteolysis-mass spectrometry (LiP-MS), crosslinking mass spectrometry (XL-MS) EMBO reports High 38351373
2024 Chronic activation of adenylyl cyclase in TGAC8 cardiomyocytes activates cell-autonomous RelA-mediated NF-κB signaling, driven by calcium/PKA signaling. This leads non-cell-autonomously to activation of proinflammatory signaling in myocardial endothelial and smooth muscle cells, expansion of myocardial immune cells, elevated serum inflammatory cytokines, and changes in lymphoid organs—all preceding cardiac fibrosis. This establishes a calcium/PKA/RelA axis connecting cardiomyocyte ADCY8 activity to myocardial and systemic inflammation. TGAC8 transgenic mouse model, NF-κB/RelA pathway analysis, PKA inhibition, flow cytometry of immune cells, ELISA for cytokines, cardiac histology GeroScience Medium 38499959
2025 ADCY8 deletion by CRISPR-Cas9 in U87MG glioma cells causes a system-wide remodeling of the mitochondrial proteome, shifting metabolism away from glycolysis (Warburg effect) toward oxidative phosphorylation, as evidenced by increased oxygen consumption, elevated TCA cycle flux, and decreased glycolytic flux. This metabolic shift is driven by absence of AC8-mediated transcriptional regulation. CRISPR-Cas9 knockout, quantitative proteomics, oxygen consumption rate measurement, metabolic flux analysis (TCA cycle, glycolysis) Biochimica et biophysica acta. Bioenergetics Medium 40669556
2025 Adcy8 knockout (Adcy8-/-) mice show more severe lipid accumulation under normal and high-fat diet conditions. ADCY8 regulates lipolysis in adipose tissue via the cAMP-PKA signaling pathway, controlling phosphorylation of lipolytic enzymes. Forskolin enhanced lipolysis and reduced adipocyte size in diet-induced obese wild-type mice but not in Adcy8-/- mice, demonstrating that ADCY8 is required for cAMP-PKA-mediated lipolytic responses in adipose tissue. Adcy8 knockout mouse model, high-fat diet feeding, adipose tissue histology, cAMP measurement, PKA substrate phosphorylation assays, forskolin stimulation Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 40527393
2024 AC8 mRNA expression is upregulated in NMDAR-2B (Nr2b)-positive neurons in the contralateral anterior cingulate cortex (ACC) of mice after spared nerve injury, while AC1 expression is unchanged, suggesting an unappreciated role for ADCY8 in ACC synaptic plasticity changes associated with neuropathic pain. RNAscope in situ hybridization in spared nerve injury mouse model, cell-type-specific co-labeling Neurobiology of pain Low 35005298
2024 Lysosomal Ca²⁺ signaling (via the NAADP pathway) contributes to α-adrenergic (phenylephrine)-stimulated cAMP production in atrial myocytes through AC1 and AC8. Double knockout of Adcy1 and Adcy8 in mice reduced the positive chronotropic and inotropic response to phenylephrine in atrial tissue, decreased Ca²⁺ transient amplitude, and abolished cytosolic cAMP elevation in neonatal atrial myocytes. This response was atrium-specific (not seen in ventricular myocytes). Adcy1/Adcy8 double-knockout mouse model, NAADP pathway inhibitors (BZ-194, SAN4825, Bafilomycin A1), cAMP FRET imaging, Ca²⁺ transient measurement, chronotropy/inotropy measurement in atrial tissue bioRxivpreprint Medium bio_10.1101_2024.11.25.625232

Source papers

Stage 0 corpus · 80 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1990 cAMP-dependent protein kinase: framework for a diverse family of regulatory enzymes. Annual review of biochemistry 1019 2165385
2009 A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 843 19490893
2000 DNA cloning using in vitro site-specific recombination. Genome research 815 11076863
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1997 Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS. Science (New York, N.Y.) 657 9417641
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2003 Glucagon and regulation of glucose metabolism. American journal of physiology. Endocrinology and metabolism 635 12626323
2006 Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 517 17110338
2002 Isoforms of mammalian adenylyl cyclase: multiplicities of signaling. Molecular interventions 299 14993377
1994 Type VIII adenylyl cyclase. A Ca2+/calmodulin-stimulated enzyme expressed in discrete regions of rat brain. The Journal of biological chemistry 278 8163524
2018 Subcellular localization of MC4R with ADCY3 at neuronal primary cilia underlies a common pathway for genetic predisposition to obesity. Nature genetics 202 29311635
2018 Loss-of-function variants in ADCY3 increase risk of obesity and type 2 diabetes. Nature genetics 146 29311636
2018 Loss-of-function mutations in ADCY3 cause monogenic severe obesity. Nature genetics 135 29311637
2010 Genome-wide association with MRI atrophy measures as a quantitative trait locus for Alzheimer's disease. Molecular psychiatry 127 21116278
2012 Direct binding between Orai1 and AC8 mediates dynamic interplay between Ca2+ and cAMP signaling. Science signaling 110 22494970
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
1994 Mechanism of GTP hydrolysis by G-protein alpha subunits. Proceedings of the National Academy of Sciences of the United States of America 106 7937899
2020 Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases. Molecular cell 88 32707033
2009 Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis. European journal of human genetics : EJHG 84 19156168
1996 Purification and characterization of a soluble form of mammalian adenylyl cyclase. The Journal of biological chemistry 83 8663304
2014 Genome-wide association study of height-adjusted BMI in childhood identifies functional variant in ADCY3. Obesity (Silver Spring, Md.) 81 25044758
2002 Characterization of the human adenylyl cyclase gene family: cDNA, gene structure, and tissue distribution of the nine isoforms. Journal of receptor and signal transduction research 77 12503609
1999 Calmodulin-binding sites on adenylyl cyclase type VIII. The Journal of biological chemistry 70 10075700
2015 Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat. International journal of obesity (2005) 68 26480920
1993 A novel adenylyl cyclase sequence cloned from the human erythroleukemia cell line. Biochemical and biophysical research communications 68 8476432
2010 AKAP79/150 interacts with AC8 and regulates Ca2+-dependent cAMP synthesis in pancreatic and neuronal systems. The Journal of biological chemistry 66 20410303
2010 Adenylyl cyclase 8 is central to glucagon-like peptide 1 signalling and effects of chronically elevated glucose in rat and human pancreatic beta cells. Diabetologia 64 21046358
2014 A genome-wide association study of clinical symptoms of dissociation in a trauma-exposed sample. Depression and anxiety 58 24677629
2003 Cyclic AMP compartmentation due to increased cAMP-phosphodiesterase activity in transgenic mice with a cardiac-directed expression of the human adenylyl cyclase type 8 (AC8). FASEB journal : official publication of the Federation of American Societies for Experimental Biology 58 12890691
2009 Capacitative Ca2+ entry via Orai1 and stromal interacting molecule 1 (STIM1) regulates adenylyl cyclase type 8. Molecular pharmacology 57 19171672
2002 Mechanism of human immunodeficiency virus-induced complement expression in astrocytes and neurons. Journal of virology 56 11884542
2018 Loss of cardiac Wnt/β-catenin signalling in desmoplakin-deficient AC8 zebrafish models is rescuable by genetic and pharmacological intervention. Cardiovascular research 46 29522173
2009 Interspecies trait genetics reveals association of Adcy8 with mouse avoidance behavior and a human mood disorder. Biological psychiatry 46 19691954
2008 Distinct mechanisms of regulation by Ca2+/calmodulin of type 1 and 8 adenylyl cyclases support their different physiological roles. The Journal of biological chemistry 46 19029295
2008 A specific role for Ca2+-dependent adenylyl cyclases in recovery from adaptive presynaptic silencing. The Journal of neuroscience : the official journal of the Society for Neuroscience 45 18480272
2013 Upregulation of adenylate cyclase 3 (ADCY3) increases the tumorigenic potential of cells by activating the CREB pathway. Oncotarget 44 24113161
2014 Genome-wide data reveal novel genes for methotrexate response in a large cohort of juvenile idiopathic arthritis cases. The pharmacogenomics journal 42 24709693
2000 HIV-1 envelope protein gp41 modulates expression of interleukin-10 and chemokine receptors on monocytes, astrocytes and neurones. AIDS (London, England) 40 10807185
2005 A direct interaction between the N terminus of adenylyl cyclase AC8 and the catalytic subunit of protein phosphatase 2A. Molecular pharmacology 38 16258073
2002 Augmentation of cardiac contractility with no change in L-type Ca2+ current in transgenic mice with a cardiac-directed expression of the human adenylyl cyclase type 8 (AC8). FASEB journal : official publication of the Federation of American Societies for Experimental Biology 37 12206999
2012 Genetic markers of comorbid depression and alcoholism in women. Alcoholism, clinical and experimental research 35 23278386
2005 Spatiotemporal localization of the calcium-stimulated adenylate cyclases, AC1 and AC8, during mouse brain development. The Journal of comparative neurology 35 15844169
2012 A key phosphorylation site in AC8 mediates regulation of Ca(2+)-dependent cAMP dynamics by an AC8-AKAP79-PKA signalling complex. Journal of cell science 29 22976297
2010 The calmodulin-stimulated adenylate cyclase ADCY8 sets the sensitivity of zebrafish retinal axons to midline repellents and is required for normal midline crossing. The Journal of neuroscience : the official journal of the Society for Neuroscience 29 20505109
2013 1H NMR-based metabolomics studies of urine reveal differences between type 1 diabetic patients with high and low HbAc1 values. Journal of pharmaceutical and biomedical analysis 27 23702564
2018 Interaction between an ADCY3 Genetic Variant and Two Weight-Lowering Diets Affecting Body Fatness and Body Composition Outcomes Depending on Macronutrient Distribution: A Randomized Trial. Nutrients 26 29921800
2016 Molecular Pap smear: HPV genotype and DNA methylation of ADCY8, CDH8, and ZNF582 as an integrated biomarker for high-grade cervical cytology. Clinical epigenetics 26 27651839
2019 LINC00319 acts as a microRNA-335-5p sponge to accelerate tumor growth and metastasis in gastric cancer by upregulating ADCY3. American journal of physiology. Gastrointestinal and liver physiology 20 31433213
2012 The Notch pathway attenuates interleukin 1β (IL1β)-mediated induction of adenylyl cyclase 8 (AC8) expression during vascular smooth muscle cell (VSMC) trans-differentiation. The Journal of biological chemistry 20 22613711
2022 A remarkable adaptive paradigm of heart performance and protection emerges in response to marked cardiac-specific overexpression of ADCY8. eLife 19 36515265
2021 Molecular modelling of novel ADCY3 variant predicts a molecular target for tackling obesity. International journal of molecular medicine 16 34821371
2024 Regulatory sites of CaM-sensitive adenylyl cyclase AC8 revealed by cryo-EM and structural proteomics. EMBO reports 13 38351373
2024 Postnatal Dynamic Ciliary ARL13B and ADCY3 Localization in the Mouse Brain. Cells 11 38334651
2021 Evaluation of calcium-sensitive adenylyl cyclase AC1 and AC8 mRNA expression in the anterior cingulate cortex of mice with spared nerve injury neuropathy. Neurobiology of pain (Cambridge, Mass.) 9 35005298
2020 Molecular Pap Smear: Validation of HPV Genotype and Host Methylation Profiles of ADCY8, CDH8, and ZNF582 as a Predictor of Cervical Cytopathology. Frontiers in microbiology 8 33178175
2019 Structural and Functional Determinants of AC8 Trafficking, Targeting and Responsiveness in Lipid Raft Microdomains. The Journal of membrane biology 7 30746562
2024 ADCY3: the pivotal gene in classical ketogenic diet for the treatment of epilepsy. Frontiers in cellular neuroscience 6 38841200
2024 RelA-mediated signaling connects adaptation to chronic cardiomyocyte stress with myocardial and systemic inflammation in the ADCY8 model of accelerated aging. GeroScience 5 38499959
2021 The Orai1-AC8 Interplay: How Breast Cancer Cells Escape from Orai1 Channel Inactivation. Cells 5 34070268
2014 Evaluation of biocompatibility of the AC8 peptide and its potential use as a drug carrier. Molecular pharmaceutics 5 25055061
2022 Polymorphism in ovine ADCY8 gene and its association with residual feed intake in Hu sheep. Animal biotechnology 4 36384395
2021 ALDH2, ADCY3 and BCMO1 polymorphisms and lifestyle-induced traits are jointly associated with CAD risk in Chinese Han people. Gene 4 34481002
2023 A Rare Case of Monogenic Obesity Due to a Novel Variant in the ADCY3 Gene: Challenges in Follow-up and Treatment. Journal of clinical research in pediatric endocrinology 3 37855273
2024 Functional Evaluation of a Novel Homozygous ADCY3 Variant Causing Childhood Obesity. International journal of molecular sciences 2 39519366
2024 Protein-coding mutation in Adcy3 increases adiposity and alters emotional behaviors sex-dependently in rats. Obesity (Silver Spring, Md.) 2 39632398
2024 Network-based meta-analysis and confirmation of genes ATP1A2, FXYD1, and ADCY3 associated with cAMP signaling in breast tumors compared to corresponding normal marginal tissues. Cellular and molecular biology (Noisy-le-Grand, France) 2 39707785
2012 The AC8 IgG3 monoclonal anti-cholesterol antibody modulates uptake and presentation of antigens for T cell activation. Immunology letters 2 22305930
2025 Adcy8 deficiency contributes to impaired lipolysis and an increased prevalence of obesity in mice. Biochimica et biophysica acta. Molecular and cell biology of lipids 1 40527393
2025 Transcriptome analysis reveals reduced lipid accumulation and mitochondrial metabolic remodeling in ADCY3-overexpressing adipocytes. Functional & integrative genomics 1 41350952
2024 Protein-coding mutation in Adcy3 increases adiposity and alters emotional behaviors sex-dependently in rats. bioRxiv : the preprint server for biology 1 38916175
2023 A Study of 41 Canine Orthologues of Human Genes Involved in Monogenic Obesity Reveals Marker in the ADCY3 for Body Weight in Labrador Retrievers. Veterinary sciences 1 37368776
2026 The rs713586 risk variant dysregulates ADCY3 rather than DNAJC27, leading to obesity through ZFP42-TET1-mediated DNA methylation. EBioMedicine 0 41494241
2026 An Adcy3 coding mutation causes partial loss of enzymatic function, contributing to obesity in a rat model by reducing lipolysis. Research square 0 41542040
2025 Deletion of AC8 in glioma cells elevates oxidative phosphorylation by system-wide remodeling of the mitochondrial proteome. Biochimica et biophysica acta. Bioenergetics 0 40669556
2025 ADCY3 Ser107Pro links difficulty awakening in the morning to adiposity through circadian regulation of adipose thermogenesis. bioRxiv : the preprint server for biology 0 40766578
2025 Meta-analysis of GLP1R, GIPR, ADCY3, and CREB1 expression in osteoarthritis identifies CREB1 as a potential biomarker and therapeutic target. Journal of clinical orthopaedics and trauma 0 41245346
2025 Circadian ADCY3 Ser107Pro variant bridges difficulty awakening in the morning and adiposity. iScience 0 41630919
2024 The association between dietary, physical activity and the DNA methylation of PPARGC1A, HLA-DQA1 and ADCY3 in pregnant women with gestational diabetes mellitus: a nest case-control study. BMC pregnancy and childbirth 0 39060963
2024 [Association between ADCY3 gene polymorphism and the effects of high-intensity interval training on body composition]. Sheng li xue bao : [Acta physiologica Sinica] 0 39780573