{"gene":"ADCY1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2007,"finding":"AC1 (ADCY1) is selectively expressed in guinea-pig sino-atrial node (SAN) cells but not ventricular muscle, where it localizes to the membrane and modulates the pacemaker current I(f) through Ca2+-stimulated cAMP production; buffering cytosolic Ca2+ with BAPTA shifted I(f) activation in the hyperpolarizing direction and abolished further inhibition by AC inhibitor MDL, demonstrating functional Ca2+-stimulated AC activity in pacemaking.","method":"RT-PCR, immunoblotting, confocal immunofluorescence, patch-clamp electrophysiology with pharmacological inhibitors (MDL 12330A, IBMX, BAPTA-AM, forskolin)","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (protein localization, electrophysiology, pharmacological dissection) in a single rigorous study","pmids":["17540702"],"is_preprint":false},{"year":2014,"finding":"ADCY1 loss-of-function (nonsense mutation p.Arg1038*) in humans causes recessive hearing impairment by disrupting the enzymatic catalytic domain and calmodulin-stimulation; ADCY1 localizes to the cytoplasm of supporting cells, hair cells, cochlear hair cell nuclei, and stereocilia; the carboxyl tail of ADCY1 is essential for localization to actin-based microvilli as shown in COS-7 cell experiments; zebrafish adcy1b morphants show loss of FM1-43 dye uptake and startle response, indicating hair cell dysfunction.","method":"Whole-exome sequencing, immunofluorescence localization, COS-7 cell overexpression/truncation assays, zebrafish morpholino knockdown with FM1-43 uptake and behavioral assays","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods across human genetics, cell biology, and animal model","pmids":["24482543"],"is_preprint":false},{"year":2015,"finding":"Activation of α7 nicotinic acetylcholine receptors (nAChRs) increases intracellular cAMP levels in hippocampal neurons via AC1 in a Ca2+-dependent manner; the Ca2+ chelator BAPTA and selective AC1 inhibitor CB-6673567 both abolished the choline-induced cAMP rise, and siRNA-mediated deletion of AC1 blocked the effect; downstream, AC1 activation led to phosphorylation of synapsin to regulate neurotransmitter release.","method":"FRET-based cAMP biosensor live-cell imaging, pharmacological inhibition (MLA antagonist, BAPTA, selective AC1 inhibitor CB-6673567), siRNA knockdown, synapsin phosphorylation assay","journal":"Neuropharmacology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (live biosensor, pharmacology, siRNA, downstream signaling) in single study","pmids":["25937212"],"is_preprint":false},{"year":2017,"finding":"In Fmr1 knockout neurons (model of Fragile X syndrome), ADCY1 mRNA translation is enhanced due to loss of FMRP, leading to excess ADCY1 protein and aberrant ERK1/2 and PI3K signaling; genetic reduction of Adcy1 normalizes ERK1/2/PI3K signaling, attenuates excessive protein synthesis, and corrects dendritic spine abnormality; behavioral deficits (repetitive behavior, defective social interaction, audiogenic seizures) were also rescued.","method":"Fmr1 knockout mice, polyribosome fractionation/mRNA translation assay, genetic Adcy1 reduction, ERK1/2 and PI3K phosphorylation assays, dendritic spine morphology, behavioral assays, pharmacological inhibition with NB001","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods across molecular, cellular, and behavioral levels in mouse genetic model","pmids":["28218269"],"is_preprint":false},{"year":2018,"finding":"ADCY1 is translocated to specific plasma membrane domains containing GPCRs, CFTR, and TMEM16A in airway epithelial cells upon GPCR stimulation, producing compartmentalized Ca2+/cAMP signals that mediate crosstalk between TMEM16A and CFTR; ADCY1 knockdown disrupted this signalosome assembly and attenuated functional coupling.","method":"siRNA knockdown of ADCY1 and GPCRs, electrophysiology (patch clamp for Cl- currents), immunofluorescence/confocal membrane localization, co-immunoprecipitation/pulldown","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 — knockdown with functional readout and localization data but single lab study","pmids":["29331508"],"is_preprint":false},{"year":2004,"finding":"Gαs-AC1 interaction is required for expression of AC1 sensitization following persistent Gαi/o-coupled receptor activation; Gαs-insensitive AC1 mutants (F293L and Y973S) retain Ca2+ and forskolin sensitivity but show markedly reduced heterologous sensitization; dominant-negative Gαs mutants disrupted D1-Gαs signaling but did not alter D2 agonist-induced sensitization, indicating sensitization involves Gαs-AC1 interactions downstream of Gαi.","method":"Site-directed mutagenesis of AC1, dominant-negative Gαs constructs, D1/D2 receptor activation in transfected cells, adenylyl cyclase activity assays","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assays combined with mutagenesis and multiple genetic perturbations","pmids":["15361543"],"is_preprint":false},{"year":2012,"finding":"AC1 (Ca2+-stimulated adenylyl cyclase) expressed in left bundle branches of atrioventricular-blocked dogs generates biological pacing by elevating cAMP; AC1 overexpression increased basal beating rate, reduced escape time, decreased dependence on electronic backup pacing, and shifted autonomic responsiveness toward parasympathetic modulation; combined AC1+HCN2 expression further enhanced pacing rate.","method":"Adenoviral gene transfer in vivo (dog AV block model), Holter ECG recordings, heart rate variability analysis","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo gene transfer with electrophysiological readouts in large animal model","pmids":["22753192"],"is_preprint":false},{"year":2017,"finding":"AC1 is required for methylglyoxal (MG)-evoked hyperalgesia but not acute nociceptive behaviors; AC1 knockout abolished MG-induced heat and mechanical hyperalgesia; pharmacological inhibition of TRPA1 reduced MG-evoked spinal p-ERK and nociception, establishing a TRPA1-AC1 sensitization mechanism in painful diabetic neuropathy.","method":"AC1 knockout mice, TRPA1 knockout mice, intrathecal pharmacology (HC030031, TRPA1 antagonist), immunohistochemistry for p-ERK in spinal cord, behavioral assays (licking/lifting, heat/mechanical hyperalgesia, conditioned place avoidance)","journal":"Frontiers in neuroscience","confidence":"High","confidence_rationale":"Tier 2 — genetic knockouts with multiple behavioral and biochemical readouts","pmids":["29270106"],"is_preprint":false},{"year":2019,"finding":"Methylglyoxal activates a spinal TRPA1-AC1-Epac signaling cascade to facilitate painful diabetic neuropathy in db/db mice; pharmacological or genetic inhibition of TRPA1, AC1, PKA, or Epac blocked MG-evoked hypersensitivity; intrathecal GERP10 (MG scavenger), HC030031 (TRPA1 inhibitor), NB001 (AC1 inhibitor), or HJC-0197 (Epac inhibitor) all attenuated hypersensitivity in db/db mice.","method":"db/db mouse model of type 2 diabetes, intrathecal pharmacological inhibitors, genetic inhibition, Ca2+ mobilization imaging in dorsal horn neurons, behavioral assays","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 2 — multiple pharmacological and genetic perturbations with cellular and behavioral readouts replicated across conditions","pmids":["30807826"],"is_preprint":false},{"year":2017,"finding":"AC1 contributes to LTP in the insular cortex (IC); postsynaptic BAPTA blocked IC LTP induction; pharmacological inhibition of AC1 (but not AC8) blocked LTP; the LTP was NMDAR-dependent and expressed postsynaptically (no change in PPR), with involvement of Ca2+-permeable AMPARs and PKMζ in expression.","method":"Whole-cell patch-clamp LTP recording in acute mouse brain slices, postsynaptic BAPTA infusion, selective AC1/AC8 inhibitors, paired-pulse ratio analysis","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 — electrophysiology with pharmacological dissection, single lab study","pmids":["28721398"],"is_preprint":false},{"year":2020,"finding":"Spinal AC1 acts downstream of NMDA receptors (NMDAR→AC1 pathway) to maintain latent sensitization of nociceptive neurons after peripheral nerve injury; AC1 deletion mutant mice showed absence of BIBO3304-induced reinstatement of mechanical hypersensitivity and conditioned place aversion; intrathecal NB001 (AC1 inhibitor) or TRPV1/TRPA1 blockers also prevented reinstatement, establishing NPY-Y1→NMDAR→AC1→TRPA1/TRPV1 signaling cascade.","method":"AC1 deletion mutant mice, NPY conditional knockdown (NPYtet/tet mice), intrathecal pharmacology (MK-801, NB001, AMG9801, HC030031), conditioned place aversion/preference assays, mechanical hypersensitivity testing","journal":"Neuropeptides","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic and pharmacological perturbations with sensory and affective behavioral readouts","pmids":["32145934"],"is_preprint":false},{"year":2000,"finding":"An ETn retrotransposon insertion in an intron of the mouse Adcy1 gene causes loss of the normal Adcy1 transcript and generates aberrant shorter transcripts due to abnormal RNA splicing and termination, confirming a loss-of-function mutation underlying the barrelless (Adcy1brl) phenotype.","method":"Northern blot analysis, phylogenetic analysis of ETn LTR sequences","journal":"Mammalian genome","confidence":"Medium","confidence_rationale":"Tier 2 — Northern blot directly demonstrating transcript loss from the genetic mutation","pmids":["10656922"],"is_preprint":false},{"year":2005,"finding":"AC1 (and AC8) exhibit spatially and temporally distinct expression patterns in mouse brain development; AC1 is broadly expressed beginning before E13 with transient expression in striatum, dorsal thalamus, trigeminal nuclei, Purkinje cells, hippocampal interneurons, and retinal ganglion cells, peaking early postnatally and then restricting to hippocampus, cerebral cortex, and cerebellar granule cells after P15.","method":"In situ hybridization across embryonic and postnatal mouse brain time points","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 3 — detailed localization study without functional consequence, but important for understanding ADCY1 biology","pmids":["15844169"],"is_preprint":false},{"year":2014,"finding":"Loss of AC1 (barrelless mutation) in mice results in increased ipsilateral corticospinal axons in dorsal and ventral medial funiculi, increased density of corticospinal motor neurons in motor cortex layer V, and enhanced locomotor recovery after spinal cord injury, indicating AC1 regulates late phases of corticospinal tract development.","method":"Anterograde and retrograde tracing of corticospinal tract in Adcy1brl mice, BMS behavioral scoring after spinal cord injury","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic loss-of-function with tract tracing and behavioral assays; single lab study","pmids":["24418466"],"is_preprint":false},{"year":2021,"finding":"MiR-19a secreted by pancreatic cancer cells via exosomes directly targets ADCY1 (and EPAC2) in pancreatic β-cells to disrupt glucose-stimulated insulin secretion; luciferase reporter assays confirmed ADCY1 as a direct miR-19a target; knockdown of ADCY1 impaired insulin secretion from MIN6 cells and primary mouse islets.","method":"Exosome isolation, luciferase reporter assay (miR-19a target validation), siRNA knockdown of Adcy1, glucose-stimulated insulin secretion assay in MIN6 cells and primary islets","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct target validation by luciferase reporter plus functional GSIS assay; single lab","pmids":["34512170"],"is_preprint":false},{"year":2022,"finding":"CUX2 transcription factor binds the ADCY1 promoter and enhances ADCY1 transcription; ChIP and dual-luciferase assays confirmed CUX2 enrichment at the ADCY1 promoter; overexpression of ADCY1 mimicked CUX2-mediated suppression of glioma cell proliferation, migration, and invasion in vitro and in vivo.","method":"Dual-luciferase reporter assay, ChIP assay, gain/loss-of-function in glioma cells (CCK8, transwell, colony formation), xenograft mouse model","journal":"Experimental brain research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and reporter assay establish direct transcriptional regulation; functional rescue experiments confirm pathway","pmids":["36242624"],"is_preprint":false},{"year":2023,"finding":"ADCY1 regulates decidualization of human endometrial stromal cells (HESCs) through the cAMP signaling pathway; siRNA knockdown of INHBB reduced ADCY1 expression and cAMP production, impairing decidualization markers; INHBB and ADCY1 expression positively correlated in RIF patient endometria; forskolin (direct AC activator) rescued the INHBB-knockdown decidualization defect.","method":"RNA-seq, siRNA knockdown of INHBB, cAMP measurement, RT-qPCR and immunofluorescence of decidual markers, Pearson correlation analysis, forskolin rescue experiment","journal":"Journal of assisted reproduction and genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 — knockdown, rescue, and correlation evidence linking INHBB-ADCY1-cAMP axis to decidualization; single lab","pmids":["36913138"],"is_preprint":false},{"year":2025,"finding":"AC1 inhibition with NB001 in the anterior cingulate cortex (ACC) of migraine rats reduced CGRP expression, alleviated periorbital mechanical thresholds, and attenuated anxiety behaviors; NMDA GluN2B receptor phosphorylation and excitatory synaptic transmission were elevated in the insular cortex of migraine rats and reduced by AC1 inhibitor hNB001.","method":"Rat chronic migraine model (dural inflammatory soup), stereotaxic ACC injection of hNB001, intraperitoneal injection, whole-cell patch-clamp recording, immunofluorescence and western blotting for CGRP and GluN2B, von Frey filament testing, open field and elevated plus maze","journal":"The journal of headache and pain","confidence":"Medium","confidence_rationale":"Tier 2 — electrophysiology plus pharmacological intervention with molecular readouts; single lab","pmids":["38760739"],"is_preprint":false},{"year":2024,"finding":"AC1 inhibitor hNB001 selectively enhanced relearning during fear extinction in aged mice but did not affect fear memory induction, expression, or recent/remote auditory fear memory; AC1 inhibition also had no effect on acute nociception, motor function, or anxiety in adult or aged mice.","method":"Trace and auditory fear conditioning/extinction in adult and aged mice, hNB001 acute and chronic oral administration, behavioral assays (von Frey, rotarod, open field)","journal":"Molecular brain","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological inhibition with multiple behavioral assays across age groups; single lab","pmids":["38389098"],"is_preprint":false},{"year":2025,"finding":"AC1 inhibition (hNB001) in the ACC reduces cortical LTP, reverses elevated NMDA GluN2B and AMPA GluA1 phosphorylation, and attenuates both presynaptic glutamate release and postsynaptic AMPAR/NMDAR responses in a migraine rat model; synaptic LTP was occluded in migraine rats, consistent with AC1-dependent cortical sensitization mediating migraine-related pain and anxiety.","method":"Whole-cell patch-clamp recording, biochemical phosphorylation assays, mEPSC recording, LTP occlusion protocol, intra-ACC injection of NB001, behavioral assays (von Frey, open field)","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — electrophysiology combined with pharmacological AC1 inhibition and biochemical readouts; single lab","pmids":["37235050"],"is_preprint":false},{"year":2025,"finding":"Montelukast (MTK) exposure in human forebrain organoids downregulates ADCY1 expression, reduces cAMP levels and neuroactivity, and causes neural maturation defects; these phenotypes were recapitulated by the selective ADCY1 inhibitor ST034307 and partially rescued by ADCY1 overexpression, establishing ADCY1-mediated cAMP signaling as the mechanistic hub for MTK's neuropsychiatric effects.","method":"Human forebrain organoids, RNA-seq, pharmacological ADCY1 inhibition (ST034307), ADCY1 overexpression, cAMP measurement, neuroactivity assays","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological inhibition and genetic rescue in human organoid model; single lab","pmids":["40471331"],"is_preprint":false},{"year":2025,"finding":"Genetic reduction of AC1 and simultaneous upregulation of KATP channel subunits (SUR1 or Kir6.2) attenuated morphine tolerance and reduced naloxone-precipitated withdrawal in mice; in vitro, inhibition of AC1 (or EPAC) enhanced KATP channel activity after chronic morphine treatment; chronic opioid-induced cAMP overshoot (heterologous sensitization) was blocked by AC1 inhibition.","method":"Genetic AC1 reduction in mice, naloxone-precipitated withdrawal assays, EPAC2-GFP-cAMP FRET biosensor in SH-SY5Y and HEK cells, thallium flux KATP channel activity assay, mouse dorsal root ganglia recordings","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — multiple complementary methods across in vitro and in vivo; preprint not yet peer reviewed","pmids":["39974972"],"is_preprint":true},{"year":2024,"finding":"AC1 inhibition blocked the rapid synaptic potentiation of Schaffer collateral-CA1 synapses induced by ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) in hippocampal slices; HNK required protein kinase A (PKA) activity and AC1 (but not AC5) activity for this rapid potentiation, which then primed synaptic plasticity to lower the LTP threshold.","method":"Extracellular electrophysiology in hippocampal slices, pharmacological inhibitors of AC1 and AC5, PKA inhibitors, in vitro incubation model with behavioral pharmacological validation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — electrophysiology with selective pharmacology; preprint not yet peer reviewed","pmids":["bio_10.1101_2024.10.18.619152"],"is_preprint":true},{"year":2024,"finding":"Lysosomal Ca2+ signaling via NAADP pathway contributes to α-adrenergic (phenylephrine)-stimulated cAMP production in atrial myocytes via AC1 and AC8; double knockout of Adcy1 and Adcy8 in mice reduced positive chronotropic and inotropic responses to phenylephrine, decreased Ca2+ transient amplitude in isolated atrial myocytes, and decreased cytosolic cAMP levels, with the NAADP pathway inhibition no longer affecting cAMP in double-KO cells.","method":"Adcy1/Adcy8 double-knockout mouse model, NAADP pathway inhibitors (BZ-194, SAN4825, bafilomycin A1), cAMP measurement in neonatal atrial myocytes, Ca2+ transient measurement, ex vivo atrial contractility","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genetic double-knockout with pharmacological dissection and multiple functional readouts; preprint","pmids":["bio_10.1101_2024.11.25.625232"],"is_preprint":true}],"current_model":"ADCY1 (AC1) is a Ca2+/calmodulin-stimulated adenylyl cyclase that converts ATP to cAMP in neurons, cardiac pacemaker cells, and inner ear hair cells; it acts downstream of NMDA receptor-mediated Ca2+ entry and α7 nAChR activation to generate compartmentalized cAMP signals that activate PKA, EPAC, and ERK1/2 signaling, thereby controlling synaptic LTP, nociceptive sensitization (via a TRPA1-AC1-Epac spinal cascade), biological cardiac pacing, hearing, and opioid tolerance, with its activity regulated by Gαs-dependent sensitization and transcriptionally controlled by CUX2."},"narrative":{"teleology":[{"year":2000,"claim":"Identifying the molecular basis of the barrelless mouse phenotype established that ADCY1 loss-of-function disrupts neural circuit refinement, providing the first genetic proof that AC1 is required for activity-dependent brain development.","evidence":"Northern blot showing ETn retrotransposon insertion abolishes normal Adcy1 transcript in barrelless mice","pmids":["10656922"],"confidence":"Medium","gaps":["Mechanism by which transcript loss causes barrel cortex defect not resolved","Protein-level confirmation not shown"]},{"year":2004,"claim":"Demonstrating that Gαs interacts directly with AC1 to produce heterologous sensitization after persistent Gαi/o signaling revealed a second mode of AC1 regulation beyond Ca²⁺/calmodulin stimulation, relevant to drug tolerance mechanisms.","evidence":"Site-directed mutagenesis of AC1 (F293L, Y973S) and dominant-negative Gαs constructs with D1/D2 receptor activation in transfected cells","pmids":["15361543"],"confidence":"High","gaps":["Structural basis of Gαs-AC1 interaction not resolved","In vivo relevance to opioid sensitization not tested in this study"]},{"year":2005,"claim":"Mapping the spatiotemporal expression of AC1 across mouse brain development revealed transient early expression in sensory relay nuclei and progressive restriction to hippocampus, cortex, and cerebellum, providing the anatomical framework for its roles in synaptic plasticity and sensory map formation.","evidence":"In situ hybridization across embryonic and postnatal mouse brain time points","pmids":["15844169"],"confidence":"Medium","gaps":["Expression data only; no functional perturbation at developmental stages","Protein-level spatial confirmation not performed"]},{"year":2007,"claim":"Demonstrating that AC1 is selectively expressed in sinoatrial node cells where it modulates pacemaker current I(f) through Ca²⁺-stimulated cAMP production established a cardiac function for AC1 outside the nervous system.","evidence":"RT-PCR, immunoblotting, confocal immunofluorescence, and patch-clamp electrophysiology with BAPTA and MDL inhibitor in guinea-pig SAN cells","pmids":["17540702"],"confidence":"High","gaps":["Genetic loss-of-function in cardiac pacemaker not tested","Human cardiac relevance not established"]},{"year":2012,"claim":"Overexpression of AC1 in canine heart generated biological pacing activity, validating AC1 as sufficient to drive cAMP-dependent automaticity and demonstrating translational potential for biological pacemaker therapy.","evidence":"Adenoviral AC1 gene transfer in AV-blocked dogs with Holter ECG recordings","pmids":["22753192"],"confidence":"Medium","gaps":["Long-term stability of biological pacing not assessed","Endogenous AC1 contribution to native pacemaking not isolated"]},{"year":2014,"claim":"Discovery that a human ADCY1 nonsense mutation causes recessive hearing impairment, combined with zebrafish knockdown phenocopying hair cell dysfunction, established AC1 as essential for auditory mechanotransduction and identified ADCY1 as a deafness gene.","evidence":"Whole-exome sequencing (p.Arg1038*), immunofluorescence in cochlea, COS-7 truncation assays, zebrafish morpholino with FM1-43 uptake and startle response","pmids":["24482543"],"confidence":"High","gaps":["Precise cAMP-dependent mechanism in hair cell stereocilia unknown","Whether other ADCY1 mutations cause deafness not explored"]},{"year":2014,"claim":"Showing that AC1 loss increases ipsilateral corticospinal projections and enhances locomotor recovery after spinal cord injury revealed a developmental role for AC1 in axon guidance that constrains adult neural repair capacity.","evidence":"Anterograde and retrograde tracing in Adcy1brl mice with BMS behavioral scoring after spinal cord injury","pmids":["24418466"],"confidence":"Medium","gaps":["Single lab study","Molecular targets downstream of AC1 in corticospinal development not identified"]},{"year":2015,"claim":"Establishing that α7 nAChR activation stimulates cAMP via AC1 in a Ca²⁺-dependent manner, leading to synapsin phosphorylation, identified AC1 as the enzymatic link coupling cholinergic Ca²⁺ signals to presynaptic neurotransmitter release regulation.","evidence":"FRET-based cAMP biosensor, BAPTA chelation, selective AC1 inhibitor CB-6673567, siRNA knockdown, and synapsin phosphorylation in hippocampal neurons","pmids":["25937212"],"confidence":"High","gaps":["In vivo behavioral consequence of α7-AC1 coupling not tested","Whether other Ca²⁺ sources access AC1 in this context unclear"]},{"year":2017,"claim":"Demonstrating that FMRP normally represses ADCY1 translation and that genetic reduction of Adcy1 rescues ERK/PI3K signaling, spine morphology, and behavioral deficits in Fragile X model mice positioned AC1 overactivity as a central mediator of Fragile X pathophysiology.","evidence":"Fmr1 KO mice, polyribosome fractionation, genetic Adcy1 reduction, ERK1/2 and PI3K phosphorylation, dendritic spine morphology, and behavioral assays","pmids":["28218269"],"confidence":"High","gaps":["Whether AC1 reduction is therapeutically viable in human FXS not tested","Relative contribution of AC1 vs. other FMRP targets unknown"]},{"year":2017,"claim":"Identifying AC1 as required for methylglyoxal-evoked hyperalgesia via a TRPA1→AC1 spinal pathway, and showing AC1 contributes to insular cortex LTP via NMDAR-dependent postsynaptic mechanisms, consolidated AC1's role as a pain sensitization hub at both spinal and cortical levels.","evidence":"AC1 and TRPA1 knockout mice with behavioral and immunohistochemical readouts; whole-cell patch-clamp LTP in insular cortex slices with selective AC1 inhibitors","pmids":["29270106","28721398"],"confidence":"High","gaps":["Spinal AC1 downstream effectors (PKA vs. Epac) not fully dissected in 2017 study","Insular cortex findings from single lab with pharmacological approach only"]},{"year":2018,"claim":"Showing AC1 translocates to plasma membrane signalosomes containing GPCRs, CFTR, and TMEM16A upon receptor stimulation in airway epithelia revealed a non-neuronal compartmentalized signaling role for AC1.","evidence":"siRNA knockdown of ADCY1, patch-clamp Cl⁻ currents, confocal localization, co-immunoprecipitation in airway epithelial cells","pmids":["29331508"],"confidence":"Medium","gaps":["Single lab study","No reciprocal Co-IP or proximity labeling for signalosome","In vivo airway relevance not tested"]},{"year":2019,"claim":"Delineating a complete spinal TRPA1→AC1→Epac cascade in diabetic neuropathy mice identified Epac as the critical cAMP effector downstream of AC1 in pain sensitization, distinguishing this pathway from canonical PKA-mediated mechanisms.","evidence":"db/db diabetic mice, intrathecal pharmacological inhibitors targeting each cascade component, Ca²⁺ imaging in dorsal horn neurons, behavioral assays","pmids":["30807826"],"confidence":"High","gaps":["Whether Epac vs. PKA selectivity is specific to MG-TRPA1 pathway or general to AC1 pain signaling unknown"]},{"year":2020,"claim":"Establishing that AC1 maintains latent nociceptive sensitization downstream of NMDA receptors after nerve injury via an NPY-Y1→NMDAR→AC1→TRPA1/TRPV1 cascade defined AC1 as the enzymatic node sustaining chronic pain vulnerability beyond the acute injury phase.","evidence":"AC1 deletion mutant mice, NPY conditional knockdown, intrathecal pharmacology with MK-801/NB001/TRP blockers, reinstatement assays","pmids":["32145934"],"confidence":"High","gaps":["Whether AC1 blockade provides lasting analgesia vs. temporary suppression unclear","Epigenetic or transcriptional regulation of AC1 in chronic pain not explored"]},{"year":2021,"claim":"Identification of ADCY1 as a direct miR-19a target in pancreatic β-cells whose knockdown impairs glucose-stimulated insulin secretion revealed AC1-dependent cAMP signaling as part of the islet secretory machinery exploited by pancreatic cancer exosomes.","evidence":"Luciferase reporter assay, siRNA knockdown of Adcy1, GSIS assay in MIN6 cells and primary mouse islets","pmids":["34512170"],"confidence":"Medium","gaps":["Single lab study","Endogenous AC1 contribution to normal GSIS vs. other adenylyl cyclases not established"]},{"year":2022,"claim":"ChIP and reporter assays showing CUX2 directly binds and activates the ADCY1 promoter identified the first transcription factor controlling ADCY1 expression, with functional consequences for tumor suppression in glioma.","evidence":"ChIP assay, dual-luciferase reporter, gain/loss-of-function in glioma cells, xenograft model","pmids":["36242624"],"confidence":"Medium","gaps":["Whether CUX2 regulates ADCY1 in normal neurons not tested","Other transcriptional regulators of ADCY1 remain unknown"]},{"year":2024,"claim":"Demonstrating that AC1 inhibition selectively enhances fear extinction relearning in aged mice without affecting memory formation or acute nociception defined a narrow therapeutic window for AC1 modulators in age-related cognitive flexibility.","evidence":"Trace and auditory fear conditioning/extinction with oral hNB001 in adult and aged mice, multiple behavioral controls","pmids":["38389098"],"confidence":"Medium","gaps":["Molecular mechanism of extinction selectivity not resolved","Single lab, single inhibitor"]},{"year":2025,"claim":"Multiple converging studies established AC1 as a cortical sensitization hub in migraine, mediating NMDA-GluN2B/AMPA-GluA1 phosphorylation and LTP in the ACC and insular cortex; separately, AC1-dependent cAMP signaling was shown essential for neural maturation in human forebrain organoids, and AC1/KATP coupling was linked to opioid tolerance.","evidence":"Rat migraine models with ACC electrophysiology and NB001 injection; human forebrain organoids with ADCY1 inhibition/overexpression; mouse genetic AC1 reduction with opioid withdrawal and KATP channel assays","pmids":["38760739","37235050","40471331","39974972"],"confidence":"Medium","gaps":["Migraine and organoid findings each from single labs","KATP-AC1 coupling data from preprint only","Human in vivo validation of AC1 inhibition for migraine or opioid tolerance absent"]},{"year":null,"claim":"Key unresolved questions include the structural basis of Ca²⁺/calmodulin activation and Gαs sensitization of AC1, the full spectrum of compartment-specific AC1 effectors (PKA vs. Epac vs. ERK) across cell types, and whether selective AC1 inhibition can achieve therapeutic benefit in pain, opioid tolerance, or neuropsychiatric conditions without disrupting essential functions in hearing and cardiac pacing.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of AC1 with calmodulin","No clinical trials of selective AC1 inhibitors","Relative contributions of AC1 vs. AC8 in overlapping expression domains not fully resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0009975","term_label":"cyclase activity","supporting_discovery_ids":[0,1,2,5,6,8]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,2,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,4,5,6,8,10]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,3,9,10,17,19]}],"complexes":[],"partners":["FMRP","TRPA1","CUX2","CFTR","TMEM16A","HCN2"],"other_free_text":[]},"mechanistic_narrative":"ADCY1 (adenylyl cyclase 1/AC1) is a Ca²⁺/calmodulin-stimulated adenylyl cyclase that converts ATP to cAMP in response to intracellular Ca²⁺ elevations, functioning as a coincidence detector that couples neuronal Ca²⁺ influx through NMDA receptors and α7 nicotinic acetylcholine receptors to compartmentalized cAMP/PKA and ERK signaling, thereby controlling synaptic long-term potentiation, fear extinction, and nociceptive sensitization [PMID:25937212, PMID:28721398, PMID:32145934, PMID:38389098]. AC1 activity is further regulated by Gαs-dependent heterologous sensitization following persistent Gαi/o-coupled receptor activation, a mechanism implicated in opioid tolerance, and its transcription is directly controlled by CUX2 [PMID:15361543, PMID:36242624]. Beyond the CNS, AC1 generates Ca²⁺-stimulated cAMP in cardiac sinoatrial node cells to modulate the pacemaker current I(f) and biological heart rate, and in inner-ear hair cells where it is required for mechanotransduction and hearing [PMID:17540702, PMID:22753192, PMID:24482543]. Biallelic loss-of-function mutations in ADCY1 cause autosomal recessive hearing impairment in humans [PMID:24482543]."},"prefetch_data":{"uniprot":{"accession":"Q08828","full_name":"Adenylate cyclase type 1","aliases":["ATP pyrophosphate-lyase 1","Adenylate cyclase type I","Adenylyl cyclase 1","Ca(2+)/calmodulin-activated adenylyl cyclase"],"length_aa":1119,"mass_kda":123.4,"function":"Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling. Mediates responses to increased cellular Ca(2+)/calmodulin levels (By similarity). May be involved in regulatory processes in the central nervous system. May play a role in memory and learning. Plays a role in the regulation of the circadian rhythm of daytime contrast sensitivity probably by modulating the rhythmic synthesis of cyclic AMP in the retina (By similarity)","subcellular_location":"Membrane; Cell membrane; Cytoplasm; Membrane raft","url":"https://www.uniprot.org/uniprotkb/Q08828/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADCY1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADCY1","total_profiled":1310},"omim":[{"mim_id":"610392","title":"MYC-BINDING PROTEIN 2; MYCBP2","url":"https://www.omim.org/entry/610392"},{"mim_id":"610154","title":"DEAFNESS, AUTOSOMAL RECESSIVE 44; 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imaging","date":"2025-05-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.18.25327845","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.03.636278","title":"Inhibition of adenylyl cyclase 1 (AC1) and exchange protein directly activated by cAMP (EPAC) restores ATP-sensitive potassium (K<sub>ATP</sub>) channel activity after chronic opioid exposure","date":"2025-02-03","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.03.636278","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.18.619152","title":"Rapid Hippocampal Synaptic Potentiation Induced by Ketamine Metabolite (<i>2R</i>,<i>6R</i>)-Hydroxynorketamine Persistently Primes Synaptic Plasticity","date":"2024-10-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.18.619152","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":37791,"output_tokens":6416,"usd":0.104806},"stage2":{"model":"claude-opus-4-6","input_tokens":10032,"output_tokens":4110,"usd":0.229365},"total_usd":0.334171,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"AC1 (ADCY1) is selectively expressed in guinea-pig sino-atrial node (SAN) cells but not ventricular muscle, where it localizes to the membrane and modulates the pacemaker current I(f) through Ca2+-stimulated cAMP production; buffering cytosolic Ca2+ with BAPTA shifted I(f) activation in the hyperpolarizing direction and abolished further inhibition by AC inhibitor MDL, demonstrating functional Ca2+-stimulated AC activity in pacemaking.\",\n      \"method\": \"RT-PCR, immunoblotting, confocal immunofluorescence, patch-clamp electrophysiology with pharmacological inhibitors (MDL 12330A, IBMX, BAPTA-AM, forskolin)\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (protein localization, electrophysiology, pharmacological dissection) in a single rigorous study\",\n      \"pmids\": [\"17540702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ADCY1 loss-of-function (nonsense mutation p.Arg1038*) in humans causes recessive hearing impairment by disrupting the enzymatic catalytic domain and calmodulin-stimulation; ADCY1 localizes to the cytoplasm of supporting cells, hair cells, cochlear hair cell nuclei, and stereocilia; the carboxyl tail of ADCY1 is essential for localization to actin-based microvilli as shown in COS-7 cell experiments; zebrafish adcy1b morphants show loss of FM1-43 dye uptake and startle response, indicating hair cell dysfunction.\",\n      \"method\": \"Whole-exome sequencing, immunofluorescence localization, COS-7 cell overexpression/truncation assays, zebrafish morpholino knockdown with FM1-43 uptake and behavioral assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods across human genetics, cell biology, and animal model\",\n      \"pmids\": [\"24482543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Activation of α7 nicotinic acetylcholine receptors (nAChRs) increases intracellular cAMP levels in hippocampal neurons via AC1 in a Ca2+-dependent manner; the Ca2+ chelator BAPTA and selective AC1 inhibitor CB-6673567 both abolished the choline-induced cAMP rise, and siRNA-mediated deletion of AC1 blocked the effect; downstream, AC1 activation led to phosphorylation of synapsin to regulate neurotransmitter release.\",\n      \"method\": \"FRET-based cAMP biosensor live-cell imaging, pharmacological inhibition (MLA antagonist, BAPTA, selective AC1 inhibitor CB-6673567), siRNA knockdown, synapsin phosphorylation assay\",\n      \"journal\": \"Neuropharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (live biosensor, pharmacology, siRNA, downstream signaling) in single study\",\n      \"pmids\": [\"25937212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Fmr1 knockout neurons (model of Fragile X syndrome), ADCY1 mRNA translation is enhanced due to loss of FMRP, leading to excess ADCY1 protein and aberrant ERK1/2 and PI3K signaling; genetic reduction of Adcy1 normalizes ERK1/2/PI3K signaling, attenuates excessive protein synthesis, and corrects dendritic spine abnormality; behavioral deficits (repetitive behavior, defective social interaction, audiogenic seizures) were also rescued.\",\n      \"method\": \"Fmr1 knockout mice, polyribosome fractionation/mRNA translation assay, genetic Adcy1 reduction, ERK1/2 and PI3K phosphorylation assays, dendritic spine morphology, behavioral assays, pharmacological inhibition with NB001\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods across molecular, cellular, and behavioral levels in mouse genetic model\",\n      \"pmids\": [\"28218269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADCY1 is translocated to specific plasma membrane domains containing GPCRs, CFTR, and TMEM16A in airway epithelial cells upon GPCR stimulation, producing compartmentalized Ca2+/cAMP signals that mediate crosstalk between TMEM16A and CFTR; ADCY1 knockdown disrupted this signalosome assembly and attenuated functional coupling.\",\n      \"method\": \"siRNA knockdown of ADCY1 and GPCRs, electrophysiology (patch clamp for Cl- currents), immunofluorescence/confocal membrane localization, co-immunoprecipitation/pulldown\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — knockdown with functional readout and localization data but single lab study\",\n      \"pmids\": [\"29331508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Gαs-AC1 interaction is required for expression of AC1 sensitization following persistent Gαi/o-coupled receptor activation; Gαs-insensitive AC1 mutants (F293L and Y973S) retain Ca2+ and forskolin sensitivity but show markedly reduced heterologous sensitization; dominant-negative Gαs mutants disrupted D1-Gαs signaling but did not alter D2 agonist-induced sensitization, indicating sensitization involves Gαs-AC1 interactions downstream of Gαi.\",\n      \"method\": \"Site-directed mutagenesis of AC1, dominant-negative Gαs constructs, D1/D2 receptor activation in transfected cells, adenylyl cyclase activity assays\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assays combined with mutagenesis and multiple genetic perturbations\",\n      \"pmids\": [\"15361543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"AC1 (Ca2+-stimulated adenylyl cyclase) expressed in left bundle branches of atrioventricular-blocked dogs generates biological pacing by elevating cAMP; AC1 overexpression increased basal beating rate, reduced escape time, decreased dependence on electronic backup pacing, and shifted autonomic responsiveness toward parasympathetic modulation; combined AC1+HCN2 expression further enhanced pacing rate.\",\n      \"method\": \"Adenoviral gene transfer in vivo (dog AV block model), Holter ECG recordings, heart rate variability analysis\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo gene transfer with electrophysiological readouts in large animal model\",\n      \"pmids\": [\"22753192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AC1 is required for methylglyoxal (MG)-evoked hyperalgesia but not acute nociceptive behaviors; AC1 knockout abolished MG-induced heat and mechanical hyperalgesia; pharmacological inhibition of TRPA1 reduced MG-evoked spinal p-ERK and nociception, establishing a TRPA1-AC1 sensitization mechanism in painful diabetic neuropathy.\",\n      \"method\": \"AC1 knockout mice, TRPA1 knockout mice, intrathecal pharmacology (HC030031, TRPA1 antagonist), immunohistochemistry for p-ERK in spinal cord, behavioral assays (licking/lifting, heat/mechanical hyperalgesia, conditioned place avoidance)\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockouts with multiple behavioral and biochemical readouts\",\n      \"pmids\": [\"29270106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Methylglyoxal activates a spinal TRPA1-AC1-Epac signaling cascade to facilitate painful diabetic neuropathy in db/db mice; pharmacological or genetic inhibition of TRPA1, AC1, PKA, or Epac blocked MG-evoked hypersensitivity; intrathecal GERP10 (MG scavenger), HC030031 (TRPA1 inhibitor), NB001 (AC1 inhibitor), or HJC-0197 (Epac inhibitor) all attenuated hypersensitivity in db/db mice.\",\n      \"method\": \"db/db mouse model of type 2 diabetes, intrathecal pharmacological inhibitors, genetic inhibition, Ca2+ mobilization imaging in dorsal horn neurons, behavioral assays\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological and genetic perturbations with cellular and behavioral readouts replicated across conditions\",\n      \"pmids\": [\"30807826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AC1 contributes to LTP in the insular cortex (IC); postsynaptic BAPTA blocked IC LTP induction; pharmacological inhibition of AC1 (but not AC8) blocked LTP; the LTP was NMDAR-dependent and expressed postsynaptically (no change in PPR), with involvement of Ca2+-permeable AMPARs and PKMζ in expression.\",\n      \"method\": \"Whole-cell patch-clamp LTP recording in acute mouse brain slices, postsynaptic BAPTA infusion, selective AC1/AC8 inhibitors, paired-pulse ratio analysis\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — electrophysiology with pharmacological dissection, single lab study\",\n      \"pmids\": [\"28721398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Spinal AC1 acts downstream of NMDA receptors (NMDAR→AC1 pathway) to maintain latent sensitization of nociceptive neurons after peripheral nerve injury; AC1 deletion mutant mice showed absence of BIBO3304-induced reinstatement of mechanical hypersensitivity and conditioned place aversion; intrathecal NB001 (AC1 inhibitor) or TRPV1/TRPA1 blockers also prevented reinstatement, establishing NPY-Y1→NMDAR→AC1→TRPA1/TRPV1 signaling cascade.\",\n      \"method\": \"AC1 deletion mutant mice, NPY conditional knockdown (NPYtet/tet mice), intrathecal pharmacology (MK-801, NB001, AMG9801, HC030031), conditioned place aversion/preference assays, mechanical hypersensitivity testing\",\n      \"journal\": \"Neuropeptides\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacological perturbations with sensory and affective behavioral readouts\",\n      \"pmids\": [\"32145934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"An ETn retrotransposon insertion in an intron of the mouse Adcy1 gene causes loss of the normal Adcy1 transcript and generates aberrant shorter transcripts due to abnormal RNA splicing and termination, confirming a loss-of-function mutation underlying the barrelless (Adcy1brl) phenotype.\",\n      \"method\": \"Northern blot analysis, phylogenetic analysis of ETn LTR sequences\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Northern blot directly demonstrating transcript loss from the genetic mutation\",\n      \"pmids\": [\"10656922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"AC1 (and AC8) exhibit spatially and temporally distinct expression patterns in mouse brain development; AC1 is broadly expressed beginning before E13 with transient expression in striatum, dorsal thalamus, trigeminal nuclei, Purkinje cells, hippocampal interneurons, and retinal ganglion cells, peaking early postnatally and then restricting to hippocampus, cerebral cortex, and cerebellar granule cells after P15.\",\n      \"method\": \"In situ hybridization across embryonic and postnatal mouse brain time points\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — detailed localization study without functional consequence, but important for understanding ADCY1 biology\",\n      \"pmids\": [\"15844169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of AC1 (barrelless mutation) in mice results in increased ipsilateral corticospinal axons in dorsal and ventral medial funiculi, increased density of corticospinal motor neurons in motor cortex layer V, and enhanced locomotor recovery after spinal cord injury, indicating AC1 regulates late phases of corticospinal tract development.\",\n      \"method\": \"Anterograde and retrograde tracing of corticospinal tract in Adcy1brl mice, BMS behavioral scoring after spinal cord injury\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with tract tracing and behavioral assays; single lab study\",\n      \"pmids\": [\"24418466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MiR-19a secreted by pancreatic cancer cells via exosomes directly targets ADCY1 (and EPAC2) in pancreatic β-cells to disrupt glucose-stimulated insulin secretion; luciferase reporter assays confirmed ADCY1 as a direct miR-19a target; knockdown of ADCY1 impaired insulin secretion from MIN6 cells and primary mouse islets.\",\n      \"method\": \"Exosome isolation, luciferase reporter assay (miR-19a target validation), siRNA knockdown of Adcy1, glucose-stimulated insulin secretion assay in MIN6 cells and primary islets\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct target validation by luciferase reporter plus functional GSIS assay; single lab\",\n      \"pmids\": [\"34512170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CUX2 transcription factor binds the ADCY1 promoter and enhances ADCY1 transcription; ChIP and dual-luciferase assays confirmed CUX2 enrichment at the ADCY1 promoter; overexpression of ADCY1 mimicked CUX2-mediated suppression of glioma cell proliferation, migration, and invasion in vitro and in vivo.\",\n      \"method\": \"Dual-luciferase reporter assay, ChIP assay, gain/loss-of-function in glioma cells (CCK8, transwell, colony formation), xenograft mouse model\",\n      \"journal\": \"Experimental brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and reporter assay establish direct transcriptional regulation; functional rescue experiments confirm pathway\",\n      \"pmids\": [\"36242624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ADCY1 regulates decidualization of human endometrial stromal cells (HESCs) through the cAMP signaling pathway; siRNA knockdown of INHBB reduced ADCY1 expression and cAMP production, impairing decidualization markers; INHBB and ADCY1 expression positively correlated in RIF patient endometria; forskolin (direct AC activator) rescued the INHBB-knockdown decidualization defect.\",\n      \"method\": \"RNA-seq, siRNA knockdown of INHBB, cAMP measurement, RT-qPCR and immunofluorescence of decidual markers, Pearson correlation analysis, forskolin rescue experiment\",\n      \"journal\": \"Journal of assisted reproduction and genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — knockdown, rescue, and correlation evidence linking INHBB-ADCY1-cAMP axis to decidualization; single lab\",\n      \"pmids\": [\"36913138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AC1 inhibition with NB001 in the anterior cingulate cortex (ACC) of migraine rats reduced CGRP expression, alleviated periorbital mechanical thresholds, and attenuated anxiety behaviors; NMDA GluN2B receptor phosphorylation and excitatory synaptic transmission were elevated in the insular cortex of migraine rats and reduced by AC1 inhibitor hNB001.\",\n      \"method\": \"Rat chronic migraine model (dural inflammatory soup), stereotaxic ACC injection of hNB001, intraperitoneal injection, whole-cell patch-clamp recording, immunofluorescence and western blotting for CGRP and GluN2B, von Frey filament testing, open field and elevated plus maze\",\n      \"journal\": \"The journal of headache and pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — electrophysiology plus pharmacological intervention with molecular readouts; single lab\",\n      \"pmids\": [\"38760739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AC1 inhibitor hNB001 selectively enhanced relearning during fear extinction in aged mice but did not affect fear memory induction, expression, or recent/remote auditory fear memory; AC1 inhibition also had no effect on acute nociception, motor function, or anxiety in adult or aged mice.\",\n      \"method\": \"Trace and auditory fear conditioning/extinction in adult and aged mice, hNB001 acute and chronic oral administration, behavioral assays (von Frey, rotarod, open field)\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition with multiple behavioral assays across age groups; single lab\",\n      \"pmids\": [\"38389098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AC1 inhibition (hNB001) in the ACC reduces cortical LTP, reverses elevated NMDA GluN2B and AMPA GluA1 phosphorylation, and attenuates both presynaptic glutamate release and postsynaptic AMPAR/NMDAR responses in a migraine rat model; synaptic LTP was occluded in migraine rats, consistent with AC1-dependent cortical sensitization mediating migraine-related pain and anxiety.\",\n      \"method\": \"Whole-cell patch-clamp recording, biochemical phosphorylation assays, mEPSC recording, LTP occlusion protocol, intra-ACC injection of NB001, behavioral assays (von Frey, open field)\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — electrophysiology combined with pharmacological AC1 inhibition and biochemical readouts; single lab\",\n      \"pmids\": [\"37235050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Montelukast (MTK) exposure in human forebrain organoids downregulates ADCY1 expression, reduces cAMP levels and neuroactivity, and causes neural maturation defects; these phenotypes were recapitulated by the selective ADCY1 inhibitor ST034307 and partially rescued by ADCY1 overexpression, establishing ADCY1-mediated cAMP signaling as the mechanistic hub for MTK's neuropsychiatric effects.\",\n      \"method\": \"Human forebrain organoids, RNA-seq, pharmacological ADCY1 inhibition (ST034307), ADCY1 overexpression, cAMP measurement, neuroactivity assays\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition and genetic rescue in human organoid model; single lab\",\n      \"pmids\": [\"40471331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Genetic reduction of AC1 and simultaneous upregulation of KATP channel subunits (SUR1 or Kir6.2) attenuated morphine tolerance and reduced naloxone-precipitated withdrawal in mice; in vitro, inhibition of AC1 (or EPAC) enhanced KATP channel activity after chronic morphine treatment; chronic opioid-induced cAMP overshoot (heterologous sensitization) was blocked by AC1 inhibition.\",\n      \"method\": \"Genetic AC1 reduction in mice, naloxone-precipitated withdrawal assays, EPAC2-GFP-cAMP FRET biosensor in SH-SY5Y and HEK cells, thallium flux KATP channel activity assay, mouse dorsal root ganglia recordings\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple complementary methods across in vitro and in vivo; preprint not yet peer reviewed\",\n      \"pmids\": [\"39974972\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AC1 inhibition blocked the rapid synaptic potentiation of Schaffer collateral-CA1 synapses induced by ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) in hippocampal slices; HNK required protein kinase A (PKA) activity and AC1 (but not AC5) activity for this rapid potentiation, which then primed synaptic plasticity to lower the LTP threshold.\",\n      \"method\": \"Extracellular electrophysiology in hippocampal slices, pharmacological inhibitors of AC1 and AC5, PKA inhibitors, in vitro incubation model with behavioral pharmacological validation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — electrophysiology with selective pharmacology; preprint not yet peer reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.10.18.619152\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lysosomal Ca2+ signaling via NAADP pathway contributes to α-adrenergic (phenylephrine)-stimulated cAMP production in atrial myocytes via AC1 and AC8; double knockout of Adcy1 and Adcy8 in mice reduced positive chronotropic and inotropic responses to phenylephrine, decreased Ca2+ transient amplitude in isolated atrial myocytes, and decreased cytosolic cAMP levels, with the NAADP pathway inhibition no longer affecting cAMP in double-KO cells.\",\n      \"method\": \"Adcy1/Adcy8 double-knockout mouse model, NAADP pathway inhibitors (BZ-194, SAN4825, bafilomycin A1), cAMP measurement in neonatal atrial myocytes, Ca2+ transient measurement, ex vivo atrial contractility\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic double-knockout with pharmacological dissection and multiple functional readouts; preprint\",\n      \"pmids\": [\"bio_10.1101_2024.11.25.625232\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ADCY1 (AC1) is a Ca2+/calmodulin-stimulated adenylyl cyclase that converts ATP to cAMP in neurons, cardiac pacemaker cells, and inner ear hair cells; it acts downstream of NMDA receptor-mediated Ca2+ entry and α7 nAChR activation to generate compartmentalized cAMP signals that activate PKA, EPAC, and ERK1/2 signaling, thereby controlling synaptic LTP, nociceptive sensitization (via a TRPA1-AC1-Epac spinal cascade), biological cardiac pacing, hearing, and opioid tolerance, with its activity regulated by Gαs-dependent sensitization and transcriptionally controlled by CUX2.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADCY1 (adenylyl cyclase 1/AC1) is a Ca²⁺/calmodulin-stimulated adenylyl cyclase that converts ATP to cAMP in response to intracellular Ca²⁺ elevations, functioning as a coincidence detector that couples neuronal Ca²⁺ influx through NMDA receptors and α7 nicotinic acetylcholine receptors to compartmentalized cAMP/PKA and ERK signaling, thereby controlling synaptic long-term potentiation, fear extinction, and nociceptive sensitization [PMID:25937212, PMID:28721398, PMID:32145934, PMID:38389098]. AC1 activity is further regulated by Gαs-dependent heterologous sensitization following persistent Gαi/o-coupled receptor activation, a mechanism implicated in opioid tolerance, and its transcription is directly controlled by CUX2 [PMID:15361543, PMID:36242624]. Beyond the CNS, AC1 generates Ca²⁺-stimulated cAMP in cardiac sinoatrial node cells to modulate the pacemaker current I(f) and biological heart rate, and in inner-ear hair cells where it is required for mechanotransduction and hearing [PMID:17540702, PMID:22753192, PMID:24482543]. Biallelic loss-of-function mutations in ADCY1 cause autosomal recessive hearing impairment in humans [PMID:24482543].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying the molecular basis of the barrelless mouse phenotype established that ADCY1 loss-of-function disrupts neural circuit refinement, providing the first genetic proof that AC1 is required for activity-dependent brain development.\",\n      \"evidence\": \"Northern blot showing ETn retrotransposon insertion abolishes normal Adcy1 transcript in barrelless mice\",\n      \"pmids\": [\"10656922\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which transcript loss causes barrel cortex defect not resolved\", \"Protein-level confirmation not shown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that Gαs interacts directly with AC1 to produce heterologous sensitization after persistent Gαi/o signaling revealed a second mode of AC1 regulation beyond Ca²⁺/calmodulin stimulation, relevant to drug tolerance mechanisms.\",\n      \"evidence\": \"Site-directed mutagenesis of AC1 (F293L, Y973S) and dominant-negative Gαs constructs with D1/D2 receptor activation in transfected cells\",\n      \"pmids\": [\"15361543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Gαs-AC1 interaction not resolved\", \"In vivo relevance to opioid sensitization not tested in this study\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapping the spatiotemporal expression of AC1 across mouse brain development revealed transient early expression in sensory relay nuclei and progressive restriction to hippocampus, cortex, and cerebellum, providing the anatomical framework for its roles in synaptic plasticity and sensory map formation.\",\n      \"evidence\": \"In situ hybridization across embryonic and postnatal mouse brain time points\",\n      \"pmids\": [\"15844169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Expression data only; no functional perturbation at developmental stages\", \"Protein-level spatial confirmation not performed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that AC1 is selectively expressed in sinoatrial node cells where it modulates pacemaker current I(f) through Ca²⁺-stimulated cAMP production established a cardiac function for AC1 outside the nervous system.\",\n      \"evidence\": \"RT-PCR, immunoblotting, confocal immunofluorescence, and patch-clamp electrophysiology with BAPTA and MDL inhibitor in guinea-pig SAN cells\",\n      \"pmids\": [\"17540702\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genetic loss-of-function in cardiac pacemaker not tested\", \"Human cardiac relevance not established\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Overexpression of AC1 in canine heart generated biological pacing activity, validating AC1 as sufficient to drive cAMP-dependent automaticity and demonstrating translational potential for biological pacemaker therapy.\",\n      \"evidence\": \"Adenoviral AC1 gene transfer in AV-blocked dogs with Holter ECG recordings\",\n      \"pmids\": [\"22753192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Long-term stability of biological pacing not assessed\", \"Endogenous AC1 contribution to native pacemaking not isolated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that a human ADCY1 nonsense mutation causes recessive hearing impairment, combined with zebrafish knockdown phenocopying hair cell dysfunction, established AC1 as essential for auditory mechanotransduction and identified ADCY1 as a deafness gene.\",\n      \"evidence\": \"Whole-exome sequencing (p.Arg1038*), immunofluorescence in cochlea, COS-7 truncation assays, zebrafish morpholino with FM1-43 uptake and startle response\",\n      \"pmids\": [\"24482543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise cAMP-dependent mechanism in hair cell stereocilia unknown\", \"Whether other ADCY1 mutations cause deafness not explored\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showing that AC1 loss increases ipsilateral corticospinal projections and enhances locomotor recovery after spinal cord injury revealed a developmental role for AC1 in axon guidance that constrains adult neural repair capacity.\",\n      \"evidence\": \"Anterograde and retrograde tracing in Adcy1brl mice with BMS behavioral scoring after spinal cord injury\",\n      \"pmids\": [\"24418466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab study\", \"Molecular targets downstream of AC1 in corticospinal development not identified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing that α7 nAChR activation stimulates cAMP via AC1 in a Ca²⁺-dependent manner, leading to synapsin phosphorylation, identified AC1 as the enzymatic link coupling cholinergic Ca²⁺ signals to presynaptic neurotransmitter release regulation.\",\n      \"evidence\": \"FRET-based cAMP biosensor, BAPTA chelation, selective AC1 inhibitor CB-6673567, siRNA knockdown, and synapsin phosphorylation in hippocampal neurons\",\n      \"pmids\": [\"25937212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo behavioral consequence of α7-AC1 coupling not tested\", \"Whether other Ca²⁺ sources access AC1 in this context unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that FMRP normally represses ADCY1 translation and that genetic reduction of Adcy1 rescues ERK/PI3K signaling, spine morphology, and behavioral deficits in Fragile X model mice positioned AC1 overactivity as a central mediator of Fragile X pathophysiology.\",\n      \"evidence\": \"Fmr1 KO mice, polyribosome fractionation, genetic Adcy1 reduction, ERK1/2 and PI3K phosphorylation, dendritic spine morphology, and behavioral assays\",\n      \"pmids\": [\"28218269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AC1 reduction is therapeutically viable in human FXS not tested\", \"Relative contribution of AC1 vs. other FMRP targets unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying AC1 as required for methylglyoxal-evoked hyperalgesia via a TRPA1→AC1 spinal pathway, and showing AC1 contributes to insular cortex LTP via NMDAR-dependent postsynaptic mechanisms, consolidated AC1's role as a pain sensitization hub at both spinal and cortical levels.\",\n      \"evidence\": \"AC1 and TRPA1 knockout mice with behavioral and immunohistochemical readouts; whole-cell patch-clamp LTP in insular cortex slices with selective AC1 inhibitors\",\n      \"pmids\": [\"29270106\", \"28721398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spinal AC1 downstream effectors (PKA vs. Epac) not fully dissected in 2017 study\", \"Insular cortex findings from single lab with pharmacological approach only\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing AC1 translocates to plasma membrane signalosomes containing GPCRs, CFTR, and TMEM16A upon receptor stimulation in airway epithelia revealed a non-neuronal compartmentalized signaling role for AC1.\",\n      \"evidence\": \"siRNA knockdown of ADCY1, patch-clamp Cl⁻ currents, confocal localization, co-immunoprecipitation in airway epithelial cells\",\n      \"pmids\": [\"29331508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab study\", \"No reciprocal Co-IP or proximity labeling for signalosome\", \"In vivo airway relevance not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Delineating a complete spinal TRPA1→AC1→Epac cascade in diabetic neuropathy mice identified Epac as the critical cAMP effector downstream of AC1 in pain sensitization, distinguishing this pathway from canonical PKA-mediated mechanisms.\",\n      \"evidence\": \"db/db diabetic mice, intrathecal pharmacological inhibitors targeting each cascade component, Ca²⁺ imaging in dorsal horn neurons, behavioral assays\",\n      \"pmids\": [\"30807826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Epac vs. PKA selectivity is specific to MG-TRPA1 pathway or general to AC1 pain signaling unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing that AC1 maintains latent nociceptive sensitization downstream of NMDA receptors after nerve injury via an NPY-Y1→NMDAR→AC1→TRPA1/TRPV1 cascade defined AC1 as the enzymatic node sustaining chronic pain vulnerability beyond the acute injury phase.\",\n      \"evidence\": \"AC1 deletion mutant mice, NPY conditional knockdown, intrathecal pharmacology with MK-801/NB001/TRP blockers, reinstatement assays\",\n      \"pmids\": [\"32145934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether AC1 blockade provides lasting analgesia vs. temporary suppression unclear\", \"Epigenetic or transcriptional regulation of AC1 in chronic pain not explored\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of ADCY1 as a direct miR-19a target in pancreatic β-cells whose knockdown impairs glucose-stimulated insulin secretion revealed AC1-dependent cAMP signaling as part of the islet secretory machinery exploited by pancreatic cancer exosomes.\",\n      \"evidence\": \"Luciferase reporter assay, siRNA knockdown of Adcy1, GSIS assay in MIN6 cells and primary mouse islets\",\n      \"pmids\": [\"34512170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab study\", \"Endogenous AC1 contribution to normal GSIS vs. other adenylyl cyclases not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"ChIP and reporter assays showing CUX2 directly binds and activates the ADCY1 promoter identified the first transcription factor controlling ADCY1 expression, with functional consequences for tumor suppression in glioma.\",\n      \"evidence\": \"ChIP assay, dual-luciferase reporter, gain/loss-of-function in glioma cells, xenograft model\",\n      \"pmids\": [\"36242624\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CUX2 regulates ADCY1 in normal neurons not tested\", \"Other transcriptional regulators of ADCY1 remain unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that AC1 inhibition selectively enhances fear extinction relearning in aged mice without affecting memory formation or acute nociception defined a narrow therapeutic window for AC1 modulators in age-related cognitive flexibility.\",\n      \"evidence\": \"Trace and auditory fear conditioning/extinction with oral hNB001 in adult and aged mice, multiple behavioral controls\",\n      \"pmids\": [\"38389098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of extinction selectivity not resolved\", \"Single lab, single inhibitor\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Multiple converging studies established AC1 as a cortical sensitization hub in migraine, mediating NMDA-GluN2B/AMPA-GluA1 phosphorylation and LTP in the ACC and insular cortex; separately, AC1-dependent cAMP signaling was shown essential for neural maturation in human forebrain organoids, and AC1/KATP coupling was linked to opioid tolerance.\",\n      \"evidence\": \"Rat migraine models with ACC electrophysiology and NB001 injection; human forebrain organoids with ADCY1 inhibition/overexpression; mouse genetic AC1 reduction with opioid withdrawal and KATP channel assays\",\n      \"pmids\": [\"38760739\", \"37235050\", \"40471331\", \"39974972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Migraine and organoid findings each from single labs\", \"KATP-AC1 coupling data from preprint only\", \"Human in vivo validation of AC1 inhibition for migraine or opioid tolerance absent\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of Ca²⁺/calmodulin activation and Gαs sensitization of AC1, the full spectrum of compartment-specific AC1 effectors (PKA vs. Epac vs. ERK) across cell types, and whether selective AC1 inhibition can achieve therapeutic benefit in pain, opioid tolerance, or neuropsychiatric conditions without disrupting essential functions in hearing and cardiac pacing.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of AC1 with calmodulin\", \"No clinical trials of selective AC1 inhibitors\", \"Relative contributions of AC1 vs. AC8 in overlapping expression domains not fully resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0009975\", \"supporting_discovery_ids\": [0, 1, 2, 5, 6, 8]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 2, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 4, 5, 6, 8, 10]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 3, 9, 10, 17, 19]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FMRP\",\n      \"TRPA1\",\n      \"CUX2\",\n      \"CFTR\",\n      \"TMEM16A\",\n      \"HCN2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}