{"gene":"ADCY1","run_date":"2026-06-09T22:02:41","timeline":{"discoveries":[{"year":2014,"finding":"ADCY1 encodes a Ca2+/calmodulin-stimulated adenylyl cyclase whose carboxyl tail (including conserved catalytic domain residues) is essential for enzymatic efficiency and for localization to actin-based microvilli; a nonsense mutation p.Arg1038* that removes 82 C-terminal amino acids causes loss of calmodulin stimulation and catalytic activity, and ADCY1 protein localizes to the cytoplasm, nuclei, and stereocilia of cochlear hair cells and supporting cells. Zebrafish adcy1b morphants showed absent FM1-43 dye uptake and loss of startle response, indicating ADCY1 is required for hair cell mechanotransduction.","method":"Whole-exome sequencing; ex vivo COS-7 cell localization assays with C-terminal truncation constructs; zebrafish morpholino knockdown with FM1-43 dye uptake and startle-response assays; mouse immunolocalization","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (mutagenesis/truncation, zebrafish KD functional assay, cellular localization) in a single focused study, consistent with locus mapping data","pmids":["24482543"],"is_preprint":false},{"year":2000,"finding":"An ETn retrotransposon insertion in an intron of mouse Adcy1 causes loss of the normal Adcy1 transcript via aberrant RNA splicing and premature termination, producing shorter non-functional transcripts. This is the causative loss-of-function mutation for the barrelless (Adcy1brl) phenotype.","method":"Northern blot analysis; RT-PCR; phylogenetic analysis of ETn LTR sequences","journal":"Mammalian genome","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Northern blot directly demonstrating loss of transcript with mechanistic explanation, single lab","pmids":["10656922"],"is_preprint":false},{"year":2017,"finding":"In Fmr1 knockout neurons, FMRP loss leads to enhanced translation of Adcy1 mRNA, resulting in excess ADCY1 protein; elevated ADCY1 drives aberrant ERK1/2- and PI3K-mediated signaling, excessive protein synthesis, and dendritic spine abnormalities. Genetic reduction of Adcy1 normalizes these signaling defects and corrects autism-related behavioral symptoms (repetitive behavior, social interaction deficits, audiogenic seizures) in Fmr1 KO mice. The ADCY1-preferring inhibitor NB001 recapitulates these behavioral corrections.","method":"Fmr1/Adcy1 double-knockout genetic epistasis; polyribosome fractionation/translation assays; immunoblotting for ERK1/2, PI3K pathway; dendritic spine morphology; behavioral assays; pharmacological inhibition with NB001","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double KO, multiple orthogonal readouts (signaling, spine morphology, behavior, pharmacology) replicated across assays","pmids":["28218269"],"is_preprint":false},{"year":2018,"finding":"In airway epithelial cells, GPCR stimulation translocates Ca2+-sensitive ADCY1 (along with EPAC1) to specific plasma membrane domains containing GPCRs, CFTR, and TMEM16A, thereby generating compartmentalized cAMP signals that mediate crosstalk between Ca2+- and cAMP-dependent chloride channel activation. Knockdown of GPCRs attenuated this signalosome assembly without affecting TMEM16A or CFTR expression or membrane localization.","method":"siRNA knockdown; live-cell imaging; electrophysiology (patch-clamp); co-localization/subcellular fractionation; cAMP biosensor assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with functional readout and localization data, single lab","pmids":["29331508"],"is_preprint":false},{"year":2022,"finding":"The transcription factor CUX2 binds directly to the ADCY1 promoter and enhances ADCY1 transcription, thereby suppressing glioma cell proliferation, migration, and invasion. Silencing ADCY1 abrogated the tumor-suppressive effects of CUX2 overexpression, placing ADCY1 downstream of CUX2 in this pathway.","method":"Dual-luciferase reporter assay; ChIP assay; gain- and loss-of-function experiments; CCK-8, plate clone, and Transwell assays; xenograft mouse model","journal":"Experimental brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm direct promoter binding; genetic epistasis with rescue experiments; single lab","pmids":["36242624"],"is_preprint":false},{"year":2023,"finding":"INHBB (Inhibin Subunit Beta B) positively regulates ADCY1 expression in human endometrial stromal cells; siRNA-mediated knockdown of INHBB suppressed ADCY1-induced cAMP production and cAMP-mediated decidualization signaling, indicating that INHBB acts upstream of ADCY1 to drive decidualization.","method":"siRNA knockdown; RNA-seq; cAMP analogue (forskolin) rescue; Pearson correlation analysis; RT-qPCR; immunofluorescence","journal":"Journal of assisted reproduction and genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA epistasis with cAMP rescue and RNA-seq mechanistic profiling, single lab","pmids":["36913138"],"is_preprint":false},{"year":2024,"finding":"In neonatal rat atrial myocytes, lysosomal Ca2+ release via the NAADP pathway activates Ca2+-sensitive adenylyl cyclases AC1 (ADCY1) and AC8, linking α-adrenergic (phenylephrine) stimulation to cAMP production and positive chronotropic/inotropic responses. Double knockout of Adcy1 and Adcy8 in mice reduced PE-stimulated chronotropy, inotropy, Ca2+ transient amplitude, and cytosolic cAMP levels in atrial (but not ventricular) myocytes.","method":"Adcy1/Adcy8 double-knockout mouse model; NAADP pathway inhibitors (BZ-194, SAN4825, Bafilomycin A1); cAMP FRET biosensor; Ca2+ transient imaging; isolated atrial myocyte contractility measurements","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic double-KO with multiple functional readouts; preprint not yet peer-reviewed; atria-specific phenotype well-supported","pmids":["bio_10.1101_2024.11.25.625232"],"is_preprint":true},{"year":2025,"finding":"In human forebrain organoids, montelukast (MTK) exposure downregulates ADCY1 expression, reducing cAMP levels and neuroactivities and causing neural maturation defects. Selective pharmacological inhibition of ADCY1 with ST034307 recapitulates these defects, while ADCY1 overexpression partially rescues them, demonstrating that ADCY1-mediated cAMP signaling is the mechanistic hub for MTK-induced neuropsychiatric effects.","method":"Human forebrain organoid model; ST034307 ADCY1 inhibitor treatment; ADCY1 overexpression rescue; cAMP measurement; neuroactivity recording; transcriptomic analysis","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition plus overexpression rescue with functional cAMP and neural activity readouts; single lab, single study","pmids":["40471331"],"is_preprint":false},{"year":2024,"finding":"ADCY1 expression is elevated in lung cancer cells relative to normal cells; knockdown of ADCY1 increases cisplatin sensitivity in A549 and H1299 cells by promoting apoptosis (increased Bax, decreased Bcl2), arresting the cell cycle, and reducing proliferation.","method":"MTT assay; CCK-8 proliferation assay; flow cytometry (apoptosis and cell cycle); RNA sequencing; siRNA knockdown and overexpression in A549, H1299, A549-DDP cells","journal":"Pharmaceuticals","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional cellular assays but no direct biochemical mechanism for cAMP-to-apoptosis link established; single lab","pmids":["39338283"],"is_preprint":false}],"current_model":"ADCY1 is a Ca2+/calmodulin-stimulated adenylyl cyclase that catalyzes ATP-to-cAMP conversion; its C-terminal catalytic domain is required for both enzymatic activity and localization to actin-based microvilli/stereocilia, making it essential for inner-ear hair cell mechanotransduction; in neurons it is translationally regulated by FMRP and, when overproduced, drives aberrant ERK1/2 and PI3K signaling; in epithelial and cardiac cells it is recruited to compartmentalized plasma membrane signalosome domains upon GPCR or lysosomal Ca2+ stimulation to generate localized cAMP; its transcription is enhanced by the CUX2 transcription factor and upstream by INHBB-dependent signaling; and collectively elevated ADCY1-mediated cAMP regulates processes ranging from decidualization and neural maturation to drug sensitivity in cancer cells."},"narrative":{"mechanistic_narrative":"ADCY1 is a Ca2+/calmodulin-stimulated adenylyl cyclase that converts ATP to cAMP and serves as a context-dependent hub for localized cAMP signaling in sensory, neuronal, epithelial, and cardiac cells [PMID:24482543, PMID:29331508]. Its carboxyl-terminal catalytic domain is required both for enzymatic efficiency and calmodulin stimulation and for targeting the protein to actin-based microvilli and cochlear hair cell stereocilia; a nonsense mutation that truncates 82 C-terminal residues abolishes catalytic activity, and loss of function disrupts hair cell mechanotransduction [PMID:24482543]. ADCY1 generates compartmentalized cAMP when recruited to plasma membrane signalosomes upon GPCR stimulation, where it co-assembles with EPAC1 alongside CFTR and TMEM16A to couple Ca2+- and cAMP-dependent chloride channel signaling [PMID:29331508], and it is similarly activated downstream of NAADP-driven lysosomal Ca2+ release to mediate α-adrenergic chronotropic and inotropic responses in atrial myocytes [PMID:bio_10.1101_2024.11.25.625232]. In neurons, Adcy1 mRNA translation is repressed by FMRP; loss of FMRP elevates ADCY1 protein, driving aberrant ERK1/2- and PI3K-mediated signaling, excessive protein synthesis, dendritic spine abnormalities, and autism-related behaviors that are corrected by reducing ADCY1 [PMID:28218269], and ADCY1-mediated cAMP also governs neural maturation in human forebrain organoids [PMID:40471331]. ADCY1 transcription is enhanced by direct promoter binding of CUX2, through which it mediates tumor suppression in glioma [PMID:36242624], and is positively regulated by upstream INHBB signaling to drive cAMP-mediated decidualization in endometrial stromal cells [PMID:36913138].","teleology":[{"year":2000,"claim":"Established Adcy1 as a genetically defined locus by identifying the causative loss-of-function lesion behind the barrelless phenotype, linking the gene to neural patterning.","evidence":"Northern blot, RT-PCR, and LTR phylogenetic analysis of an ETn retrotransposon insertion in mouse Adcy1","pmids":["10656922"],"confidence":"Medium","gaps":["Does not define the biochemical activity of the lost protein","Mechanism connecting transcript loss to neural patterning not resolved"]},{"year":2014,"claim":"Defined ADCY1 as a Ca2+/calmodulin-stimulated adenylyl cyclase whose C-terminal catalytic domain governs both activity and stereocilia localization, establishing its essential role in hair cell mechanotransduction.","evidence":"Whole-exome sequencing of a deafness mutation, COS-7 truncation/localization assays, zebrafish morphant FM1-43 and startle assays, mouse immunolocalization","pmids":["24482543"],"confidence":"High","gaps":["How the C-terminus targets actin-based microvilli mechanistically is unresolved","No structural model of the catalytic domain–calmodulin interaction"]},{"year":2017,"claim":"Showed ADCY1 is a translationally repressed FMRP target whose overproduction drives the aberrant ERK1/2 and PI3K signaling and behavioral deficits of fragile X, identifying ADCY1 as a therapeutic node.","evidence":"Fmr1/Adcy1 double-KO epistasis, polyribosome translation assays, signaling immunoblots, spine morphology, behavior, and NB001 pharmacology in mice","pmids":["28218269"],"confidence":"High","gaps":["Direct biochemical link from cAMP output to ERK1/2 and PI3K activation not delineated","Whether effects are cell-autonomous to specific neuron types unaddressed"]},{"year":2018,"claim":"Demonstrated that ADCY1 is recruited into GPCR-organized plasma membrane signalosomes to produce compartmentalized cAMP, providing a mechanism for Ca2+-to-cAMP crosstalk at chloride channels.","evidence":"siRNA knockdown, live-cell imaging, patch-clamp electrophysiology, fractionation, and cAMP biosensors in airway epithelial cells","pmids":["29331508"],"confidence":"Medium","gaps":["Scaffold proteins recruiting ADCY1 to the GPCR domain not identified","Single cell type; generality across epithelia untested"]},{"year":2022,"claim":"Placed ADCY1 downstream of the CUX2 transcription factor, identifying transcriptional control of ADCY1 as a route to tumor suppression in glioma.","evidence":"Dual-luciferase reporter and ChIP for promoter binding, gain/loss-of-function rescue, proliferation/migration assays, and xenografts","pmids":["36242624"],"confidence":"Medium","gaps":["cAMP-dependence of the tumor-suppressive effect not directly tested","Downstream effectors mediating growth suppression unidentified"]},{"year":2023,"claim":"Identified INHBB as an upstream positive regulator of ADCY1 driving cAMP-mediated decidualization, extending ADCY1 signaling into reproductive biology.","evidence":"siRNA knockdown, RNA-seq, forskolin rescue, and correlation analysis in human endometrial stromal cells","pmids":["36913138"],"confidence":"Medium","gaps":["Mechanism by which INHBB regulates ADCY1 (transcriptional vs other) not defined","Direct vs indirect regulation not distinguished"]},{"year":2024,"claim":"Linked NAADP-driven lysosomal Ca2+ release to ADCY1/AC8 activation, defining a chamber-specific mechanism coupling α-adrenergic stimulation to cAMP and atrial contractility.","evidence":"Adcy1/Adcy8 double-KO mice, NAADP pathway inhibitors, cAMP FRET biosensor, Ca2+ transient imaging, and contractility in isolated myocytes (preprint)","pmids":["bio_10.1101_2024.11.25.625232"],"confidence":"Medium","gaps":["Relative contributions of ADCY1 vs AC8 not separated","Preprint not yet peer-reviewed","Spatial relationship between lysosomal Ca2+ and ADCY1 not visualized"]},{"year":2024,"claim":"Associated elevated ADCY1 with cisplatin resistance in lung cancer cells, suggesting ADCY1 modulates apoptotic and cell-cycle responses to chemotherapy.","evidence":"siRNA knockdown/overexpression, MTT/CCK-8, flow cytometry for apoptosis and cell cycle, and RNA-seq in A549/H1299 cells","pmids":["39338283"],"confidence":"Low","gaps":["No direct biochemical mechanism linking cAMP to apoptosis established","Single lab, no in vivo validation"]},{"year":2025,"claim":"Established ADCY1-mediated cAMP as the mechanistic hub for montelukast-induced neural maturation defects in a human model, reinforcing ADCY1's role in neurodevelopment.","evidence":"Human forebrain organoids with ST034307 inhibition, ADCY1 overexpression rescue, cAMP measurement, neuroactivity recording, and transcriptomics","pmids":["40471331"],"confidence":"Medium","gaps":["How montelukast downregulates ADCY1 transcription not defined","Downstream cAMP effectors driving maturation unidentified"]},{"year":null,"claim":"How ADCY1's catalytic activity, calmodulin/Ca2+ sensing, and subcellular targeting are integrated to produce the distinct compartmentalized cAMP outputs across hair cells, neurons, epithelia, and myocytes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural or scaffolding model across cell types","Effector coupling (EPAC1, PKA, channels) characterized only piecemeal","Determinants of tissue-specific signalosome assembly unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0009975","term_label":"cyclase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[0]}],"complexes":["GPCR-CFTR-TMEM16A plasma membrane signalosome"],"partners":["EPAC1","FMRP","CUX2","INHBB","ADCY8"],"other_free_text":[]}},"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; DFNB44","url":"https://www.omim.org/entry/610154"},{"mim_id":"605071","title":"REGULATOR OF G PROTEIN SIGNALING 19; RGS19","url":"https://www.omim.org/entry/605071"},{"mim_id":"601534","title":"POTASSIUM CHANNEL, INWARDLY RECTIFYING, SUBFAMILY J, MEMBER 3; KCNJ3","url":"https://www.omim.org/entry/601534"},{"mim_id":"600018","title":"OPIOID RECEPTOR, MU-1; OPRM1","url":"https://www.omim.org/entry/600018"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Mitochondria","reliability":"Uncertain"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":33.9},{"tissue":"liver","ntpm":17.8},{"tissue":"retina","ntpm":49.2}],"url":"https://www.proteinatlas.org/search/ADCY1"},"hgnc":{"alias_symbol":["AC1"],"prev_symbol":["DFNB44"]},"alphafold":{"accession":"Q08828","domains":[{"cath_id":"-","chopping":"40-83_91-141_160-271_783-835","consensus_level":"medium","plddt":88.9282,"start":40,"end":835},{"cath_id":"3.30.70.1230","chopping":"296-485_499-522","consensus_level":"medium","plddt":84.0744,"start":296,"end":522},{"cath_id":"3.30.70.1230","chopping":"861-935_943-1072","consensus_level":"medium","plddt":87.9663,"start":861,"end":1072}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08828","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q08828-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q08828-F1-predicted_aligned_error_v6.png","plddt_mean":77.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADCY1","jax_strain_url":"https://www.jax.org/strain/search?query=ADCY1"},"sequence":{"accession":"Q08828","fasta_url":"https://rest.uniprot.org/uniprotkb/Q08828.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q08828/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q08828"}},"corpus_meta":[{"pmid":"29331508","id":"PMC_29331508","title":"Compartmentalized crosstalk of CFTR and TMEM16A (ANO1) through EPAC1 and ADCY1.","date":"2018","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/29331508","citation_count":48,"is_preprint":false},{"pmid":"28218269","id":"PMC_28218269","title":"Enhanced expression of ADCY1 underlies aberrant neuronal signalling and behaviour in a syndromic autism model.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28218269","citation_count":44,"is_preprint":false},{"pmid":"24482543","id":"PMC_24482543","title":"Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24482543","citation_count":39,"is_preprint":false},{"pmid":"31839819","id":"PMC_31839819","title":"A perspective profile of ADCY1 in cAMP signaling with drug-resistance in lung cancer.","date":"2019","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31839819","citation_count":38,"is_preprint":false},{"pmid":"34512170","id":"PMC_34512170","title":"Pancreatic cancer-derived exosomal microRNA-19a induces β-cell dysfunction by targeting ADCY1 and EPAC2.","date":"2021","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34512170","citation_count":32,"is_preprint":false},{"pmid":"35076816","id":"PMC_35076816","title":"Circ-LTBP1 is involved in doxorubicin-induced intracellular toxicity in cardiomyocytes via miR-107/ADCY1 signal.","date":"2022","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35076816","citation_count":16,"is_preprint":false},{"pmid":"33744851","id":"PMC_33744851","title":"Long non-coding RNA DPP10-AS1 exerts anti-tumor effects on colon cancer via the upregulation of ADCY1 by regulating microRNA-127-3p.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33744851","citation_count":13,"is_preprint":false},{"pmid":"40424986","id":"PMC_40424986","title":"Ginsenoside Rg1 alleviates cognitive impairment in vascular dementia by modulating Adcy1/Kdr-mediated cholinergic synapse and PI3K-AKT pathway.","date":"2025","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/40424986","citation_count":11,"is_preprint":false},{"pmid":"35793187","id":"PMC_35793187","title":"Electroacupuncture Alleviates Thalamic Pain in Rats by Suppressing ADCY1 Protein Upregulation.","date":"2022","source":"Pain physician","url":"https://pubmed.ncbi.nlm.nih.gov/35793187","citation_count":10,"is_preprint":false},{"pmid":"35438054","id":"PMC_35438054","title":"LncRNA H19 acts as miR-301a-3p sponge to alleviate lung injury in mice with sepsis by regulating Adcy1.","date":"2022","source":"Immunopharmacology and immunotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/35438054","citation_count":10,"is_preprint":false},{"pmid":"10656922","id":"PMC_10656922","title":"ETn insertion in the mouse Adcy1 gene: transcriptional and phylogenetic analyses.","date":"2000","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/10656922","citation_count":10,"is_preprint":false},{"pmid":"35530157","id":"PMC_35530157","title":"Genome-wide analysis identify novel germline genetic variations in ADCY1 influencing platinum-based chemotherapy response in non-small cell lung cancer.","date":"2021","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/35530157","citation_count":10,"is_preprint":false},{"pmid":"15583425","id":"PMC_15583425","title":"DFNB44, a novel autosomal recessive non-syndromic hearing impairment locus, maps to chromosome 7p14.1-q11.22.","date":"2004","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/15583425","citation_count":9,"is_preprint":false},{"pmid":"36938448","id":"PMC_36938448","title":"MiR-1281 is involved in depression disorder and the antidepressant effects of Kai-Xin-San by targeting ADCY1 and DVL1.","date":"2023","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/36938448","citation_count":7,"is_preprint":false},{"pmid":"36913138","id":"PMC_36913138","title":"Downregulated INHBB in endometrial tissue of recurrent implantation failure patients impeded decidualization through the ADCY1/cAMP signalling pathway.","date":"2023","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36913138","citation_count":5,"is_preprint":false},{"pmid":"36242624","id":"PMC_36242624","title":"CUX2 prevents the malignant progression of gliomas by enhancing ADCY1 transcription.","date":"2022","source":"Experimental brain research","url":"https://pubmed.ncbi.nlm.nih.gov/36242624","citation_count":2,"is_preprint":false},{"pmid":"40471331","id":"PMC_40471331","title":"The ADCY1-mediated cAMP signaling pathway mediates functional effects of montelukast treatment in brain organoids.","date":"2025","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/40471331","citation_count":0,"is_preprint":false},{"pmid":"39338283","id":"PMC_39338283","title":"The Role of ADCY1 in Regulating the Sensitivity of Platinum-Based Chemotherapy in NSCLC.","date":"2024","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/39338283","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.25.625232","title":"Lysosomal calcium signalling contributes to the acute α-adrenergic response via calcium-stimulated adenylyl cyclase 1 and 8","date":"2024-11-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.25.625232","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12123,"output_tokens":2711,"usd":0.038517,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10040,"output_tokens":3681,"usd":0.071112,"stage2_stop_reason":"end_turn"},"total_usd":0.109629,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"ADCY1 encodes a Ca2+/calmodulin-stimulated adenylyl cyclase whose carboxyl tail (including conserved catalytic domain residues) is essential for enzymatic efficiency and for localization to actin-based microvilli; a nonsense mutation p.Arg1038* that removes 82 C-terminal amino acids causes loss of calmodulin stimulation and catalytic activity, and ADCY1 protein localizes to the cytoplasm, nuclei, and stereocilia of cochlear hair cells and supporting cells. Zebrafish adcy1b morphants showed absent FM1-43 dye uptake and loss of startle response, indicating ADCY1 is required for hair cell mechanotransduction.\",\n      \"method\": \"Whole-exome sequencing; ex vivo COS-7 cell localization assays with C-terminal truncation constructs; zebrafish morpholino knockdown with FM1-43 dye uptake and startle-response assays; mouse immunolocalization\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (mutagenesis/truncation, zebrafish KD functional assay, cellular localization) in a single focused study, consistent with locus mapping data\",\n      \"pmids\": [\"24482543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"An ETn retrotransposon insertion in an intron of mouse Adcy1 causes loss of the normal Adcy1 transcript via aberrant RNA splicing and premature termination, producing shorter non-functional transcripts. This is the causative loss-of-function mutation for the barrelless (Adcy1brl) phenotype.\",\n      \"method\": \"Northern blot analysis; RT-PCR; phylogenetic analysis of ETn LTR sequences\",\n      \"journal\": \"Mammalian genome\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Northern blot directly demonstrating loss of transcript with mechanistic explanation, single lab\",\n      \"pmids\": [\"10656922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Fmr1 knockout neurons, FMRP loss leads to enhanced translation of Adcy1 mRNA, resulting in excess ADCY1 protein; elevated ADCY1 drives aberrant ERK1/2- and PI3K-mediated signaling, excessive protein synthesis, and dendritic spine abnormalities. Genetic reduction of Adcy1 normalizes these signaling defects and corrects autism-related behavioral symptoms (repetitive behavior, social interaction deficits, audiogenic seizures) in Fmr1 KO mice. The ADCY1-preferring inhibitor NB001 recapitulates these behavioral corrections.\",\n      \"method\": \"Fmr1/Adcy1 double-knockout genetic epistasis; polyribosome fractionation/translation assays; immunoblotting for ERK1/2, PI3K pathway; dendritic spine morphology; behavioral assays; pharmacological inhibition with NB001\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double KO, multiple orthogonal readouts (signaling, spine morphology, behavior, pharmacology) replicated across assays\",\n      \"pmids\": [\"28218269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In airway epithelial cells, GPCR stimulation translocates Ca2+-sensitive ADCY1 (along with EPAC1) to specific plasma membrane domains containing GPCRs, CFTR, and TMEM16A, thereby generating compartmentalized cAMP signals that mediate crosstalk between Ca2+- and cAMP-dependent chloride channel activation. Knockdown of GPCRs attenuated this signalosome assembly without affecting TMEM16A or CFTR expression or membrane localization.\",\n      \"method\": \"siRNA knockdown; live-cell imaging; electrophysiology (patch-clamp); co-localization/subcellular fractionation; cAMP biosensor assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with functional readout and localization data, single lab\",\n      \"pmids\": [\"29331508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The transcription factor CUX2 binds directly to the ADCY1 promoter and enhances ADCY1 transcription, thereby suppressing glioma cell proliferation, migration, and invasion. Silencing ADCY1 abrogated the tumor-suppressive effects of CUX2 overexpression, placing ADCY1 downstream of CUX2 in this pathway.\",\n      \"method\": \"Dual-luciferase reporter assay; ChIP assay; gain- and loss-of-function experiments; CCK-8, plate clone, and Transwell assays; xenograft mouse model\",\n      \"journal\": \"Experimental brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm direct promoter binding; genetic epistasis with rescue experiments; single lab\",\n      \"pmids\": [\"36242624\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"INHBB (Inhibin Subunit Beta B) positively regulates ADCY1 expression in human endometrial stromal cells; siRNA-mediated knockdown of INHBB suppressed ADCY1-induced cAMP production and cAMP-mediated decidualization signaling, indicating that INHBB acts upstream of ADCY1 to drive decidualization.\",\n      \"method\": \"siRNA knockdown; RNA-seq; cAMP analogue (forskolin) rescue; Pearson correlation analysis; RT-qPCR; immunofluorescence\",\n      \"journal\": \"Journal of assisted reproduction and genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA epistasis with cAMP rescue and RNA-seq mechanistic profiling, single lab\",\n      \"pmids\": [\"36913138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In neonatal rat atrial myocytes, lysosomal Ca2+ release via the NAADP pathway activates Ca2+-sensitive adenylyl cyclases AC1 (ADCY1) and AC8, linking α-adrenergic (phenylephrine) stimulation to cAMP production and positive chronotropic/inotropic responses. Double knockout of Adcy1 and Adcy8 in mice reduced PE-stimulated chronotropy, inotropy, Ca2+ transient amplitude, and cytosolic cAMP levels in atrial (but not ventricular) myocytes.\",\n      \"method\": \"Adcy1/Adcy8 double-knockout mouse model; NAADP pathway inhibitors (BZ-194, SAN4825, Bafilomycin A1); cAMP FRET biosensor; Ca2+ transient imaging; isolated atrial myocyte contractility measurements\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic double-KO with multiple functional readouts; preprint not yet peer-reviewed; atria-specific phenotype well-supported\",\n      \"pmids\": [\"bio_10.1101_2024.11.25.625232\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In human forebrain organoids, montelukast (MTK) exposure downregulates ADCY1 expression, reducing cAMP levels and neuroactivities and causing neural maturation defects. Selective pharmacological inhibition of ADCY1 with ST034307 recapitulates these defects, while ADCY1 overexpression partially rescues them, demonstrating that ADCY1-mediated cAMP signaling is the mechanistic hub for MTK-induced neuropsychiatric effects.\",\n      \"method\": \"Human forebrain organoid model; ST034307 ADCY1 inhibitor treatment; ADCY1 overexpression rescue; cAMP measurement; neuroactivity recording; transcriptomic analysis\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition plus overexpression rescue with functional cAMP and neural activity readouts; single lab, single study\",\n      \"pmids\": [\"40471331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ADCY1 expression is elevated in lung cancer cells relative to normal cells; knockdown of ADCY1 increases cisplatin sensitivity in A549 and H1299 cells by promoting apoptosis (increased Bax, decreased Bcl2), arresting the cell cycle, and reducing proliferation.\",\n      \"method\": \"MTT assay; CCK-8 proliferation assay; flow cytometry (apoptosis and cell cycle); RNA sequencing; siRNA knockdown and overexpression in A549, H1299, A549-DDP cells\",\n      \"journal\": \"Pharmaceuticals\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional cellular assays but no direct biochemical mechanism for cAMP-to-apoptosis link established; single lab\",\n      \"pmids\": [\"39338283\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADCY1 is a Ca2+/calmodulin-stimulated adenylyl cyclase that catalyzes ATP-to-cAMP conversion; its C-terminal catalytic domain is required for both enzymatic activity and localization to actin-based microvilli/stereocilia, making it essential for inner-ear hair cell mechanotransduction; in neurons it is translationally regulated by FMRP and, when overproduced, drives aberrant ERK1/2 and PI3K signaling; in epithelial and cardiac cells it is recruited to compartmentalized plasma membrane signalosome domains upon GPCR or lysosomal Ca2+ stimulation to generate localized cAMP; its transcription is enhanced by the CUX2 transcription factor and upstream by INHBB-dependent signaling; and collectively elevated ADCY1-mediated cAMP regulates processes ranging from decidualization and neural maturation to drug sensitivity in cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADCY1 is a Ca2+/calmodulin-stimulated adenylyl cyclase that converts ATP to cAMP and serves as a context-dependent hub for localized cAMP signaling in sensory, neuronal, epithelial, and cardiac cells [#0, #3]. Its carboxyl-terminal catalytic domain is required both for enzymatic efficiency and calmodulin stimulation and for targeting the protein to actin-based microvilli and cochlear hair cell stereocilia; a nonsense mutation that truncates 82 C-terminal residues abolishes catalytic activity, and loss of function disrupts hair cell mechanotransduction [#0]. ADCY1 generates compartmentalized cAMP when recruited to plasma membrane signalosomes upon GPCR stimulation, where it co-assembles with EPAC1 alongside CFTR and TMEM16A to couple Ca2+- and cAMP-dependent chloride channel signaling [#3], and it is similarly activated downstream of NAADP-driven lysosomal Ca2+ release to mediate α-adrenergic chronotropic and inotropic responses in atrial myocytes [#6]. In neurons, Adcy1 mRNA translation is repressed by FMRP; loss of FMRP elevates ADCY1 protein, driving aberrant ERK1/2- and PI3K-mediated signaling, excessive protein synthesis, dendritic spine abnormalities, and autism-related behaviors that are corrected by reducing ADCY1 [#2], and ADCY1-mediated cAMP also governs neural maturation in human forebrain organoids [#7]. ADCY1 transcription is enhanced by direct promoter binding of CUX2, through which it mediates tumor suppression in glioma [#4], and is positively regulated by upstream INHBB signaling to drive cAMP-mediated decidualization in endometrial stromal cells [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established Adcy1 as a genetically defined locus by identifying the causative loss-of-function lesion behind the barrelless phenotype, linking the gene to neural patterning.\",\n      \"evidence\": \"Northern blot, RT-PCR, and LTR phylogenetic analysis of an ETn retrotransposon insertion in mouse Adcy1\",\n      \"pmids\": [\"10656922\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Does not define the biochemical activity of the lost protein\",\n        \"Mechanism connecting transcript loss to neural patterning not resolved\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined ADCY1 as a Ca2+/calmodulin-stimulated adenylyl cyclase whose C-terminal catalytic domain governs both activity and stereocilia localization, establishing its essential role in hair cell mechanotransduction.\",\n      \"evidence\": \"Whole-exome sequencing of a deafness mutation, COS-7 truncation/localization assays, zebrafish morphant FM1-43 and startle assays, mouse immunolocalization\",\n      \"pmids\": [\"24482543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How the C-terminus targets actin-based microvilli mechanistically is unresolved\",\n        \"No structural model of the catalytic domain–calmodulin interaction\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed ADCY1 is a translationally repressed FMRP target whose overproduction drives the aberrant ERK1/2 and PI3K signaling and behavioral deficits of fragile X, identifying ADCY1 as a therapeutic node.\",\n      \"evidence\": \"Fmr1/Adcy1 double-KO epistasis, polyribosome translation assays, signaling immunoblots, spine morphology, behavior, and NB001 pharmacology in mice\",\n      \"pmids\": [\"28218269\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct biochemical link from cAMP output to ERK1/2 and PI3K activation not delineated\",\n        \"Whether effects are cell-autonomous to specific neuron types unaddressed\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated that ADCY1 is recruited into GPCR-organized plasma membrane signalosomes to produce compartmentalized cAMP, providing a mechanism for Ca2+-to-cAMP crosstalk at chloride channels.\",\n      \"evidence\": \"siRNA knockdown, live-cell imaging, patch-clamp electrophysiology, fractionation, and cAMP biosensors in airway epithelial cells\",\n      \"pmids\": [\"29331508\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Scaffold proteins recruiting ADCY1 to the GPCR domain not identified\",\n        \"Single cell type; generality across epithelia untested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed ADCY1 downstream of the CUX2 transcription factor, identifying transcriptional control of ADCY1 as a route to tumor suppression in glioma.\",\n      \"evidence\": \"Dual-luciferase reporter and ChIP for promoter binding, gain/loss-of-function rescue, proliferation/migration assays, and xenografts\",\n      \"pmids\": [\"36242624\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"cAMP-dependence of the tumor-suppressive effect not directly tested\",\n        \"Downstream effectors mediating growth suppression unidentified\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified INHBB as an upstream positive regulator of ADCY1 driving cAMP-mediated decidualization, extending ADCY1 signaling into reproductive biology.\",\n      \"evidence\": \"siRNA knockdown, RNA-seq, forskolin rescue, and correlation analysis in human endometrial stromal cells\",\n      \"pmids\": [\"36913138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which INHBB regulates ADCY1 (transcriptional vs other) not defined\",\n        \"Direct vs indirect regulation not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked NAADP-driven lysosomal Ca2+ release to ADCY1/AC8 activation, defining a chamber-specific mechanism coupling α-adrenergic stimulation to cAMP and atrial contractility.\",\n      \"evidence\": \"Adcy1/Adcy8 double-KO mice, NAADP pathway inhibitors, cAMP FRET biosensor, Ca2+ transient imaging, and contractility in isolated myocytes (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.11.25.625232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Relative contributions of ADCY1 vs AC8 not separated\",\n        \"Preprint not yet peer-reviewed\",\n        \"Spatial relationship between lysosomal Ca2+ and ADCY1 not visualized\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Associated elevated ADCY1 with cisplatin resistance in lung cancer cells, suggesting ADCY1 modulates apoptotic and cell-cycle responses to chemotherapy.\",\n      \"evidence\": \"siRNA knockdown/overexpression, MTT/CCK-8, flow cytometry for apoptosis and cell cycle, and RNA-seq in A549/H1299 cells\",\n      \"pmids\": [\"39338283\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct biochemical mechanism linking cAMP to apoptosis established\",\n        \"Single lab, no in vivo validation\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established ADCY1-mediated cAMP as the mechanistic hub for montelukast-induced neural maturation defects in a human model, reinforcing ADCY1's role in neurodevelopment.\",\n      \"evidence\": \"Human forebrain organoids with ST034307 inhibition, ADCY1 overexpression rescue, cAMP measurement, neuroactivity recording, and transcriptomics\",\n      \"pmids\": [\"40471331\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How montelukast downregulates ADCY1 transcription not defined\",\n        \"Downstream cAMP effectors driving maturation unidentified\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ADCY1's catalytic activity, calmodulin/Ca2+ sensing, and subcellular targeting are integrated to produce the distinct compartmentalized cAMP outputs across hair cells, neurons, epithelia, and myocytes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unified structural or scaffolding model across cell types\",\n        \"Effector coupling (EPAC1, PKA, channels) characterized only piecemeal\",\n        \"Determinants of tissue-specific signalosome assembly unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0009975\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"GPCR-CFTR-TMEM16A plasma membrane signalosome\"\n    ],\n    \"partners\": [\n      \"EPAC1\",\n      \"FMRP\",\n      \"CUX2\",\n      \"INHBB\",\n      \"ADCY8\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}