{"gene":"ADCY10","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2006,"finding":"Soluble adenylyl cyclase (sAC/ADCY10) is the predominant source of cAMP in spermatozoa; sAC-null sperm have greatly diminished adenylyl cyclase activity and cAMP content, fail to respond to HCO3- stimulation (flagellar beat frequency, Ca2+ entry), and do not develop hyperactivated motility or capacitation-associated tyrosine phosphorylation, establishing sAC as essential for cAMP-dependent sperm capacitation and motility.","method":"sAC knockout mouse model (sAC-/- spermatozoa), adenylyl cyclase activity assays, cAMP measurement, Ca2+ imaging, flagellar beat frequency analysis, protein tyrosine phosphorylation assays, rescue with cell-permeable cAMP analogs","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods in KO model with specific phenotypic readouts, replicated across assays","pmids":["16842770"],"is_preprint":false},{"year":2007,"finding":"The sperm-specific Na+/H+ exchanger (sNHE) physically associates with sAC/ADCY10 at the sperm flagellar plasma membrane (co-immunoprecipitation and codependent expression), and sNHE is required for full-length sAC expression and for bicarbonate-stimulated sAC activity in spermatozoa, placing sNHE and sAC in the same flagellar signaling complex.","method":"Co-immunoprecipitation, sNHE-null mouse model, western blotting, adenylyl cyclase activity assay, cAMP-dependent tyrosine phosphorylation assay, motility rescue with cell-permeable cAMP analogs","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus KO model with multiple orthogonal readouts","pmids":["17517652"],"is_preprint":false},{"year":2007,"finding":"External Ca2+ is required upstream of sAC/ADCY10 (SACY) for HCO3--evoked cAMP elevation and motility activation in sperm; Ca2+ is not needed for cAMP-AM to increase beat frequency, placing extracellular Ca2+ between HCO3- stimulus and sAC activation. Carbonic anhydrase activity also facilitates rapid HCO3- action on sAC.","method":"Ca2+ removal/replacement experiments, caged-Ca2+ photolysis, carbonic anhydrase inhibitor (acetazolamide), cAMP-AM rescue, flagellar beat frequency measurement","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 1-2 — pharmacological dissection with multiple orthogonal interventions definitively ordering Ca2+ upstream of sAC","pmids":["17950270"],"is_preprint":false},{"year":2008,"finding":"Somatic tissues express a previously uncharacterized isoform of sAC/ADCY10 that uses a unique transcriptional start site and escapes deletion of exons 2-4 present in the Sacytm1Lex knockout allele, explaining the absence of somatic phenotype in that mouse line and demonstrating increased complexity at the ADCY10 locus.","method":"Immunological (western blot) and molecular biological (RT-PCR, isoform mapping) characterization of somatic tissues from Sacytm1Lex/Sacytm1Lex knockout mice","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal molecular methods identifying novel isoform in KO model","pmids":["18806876"],"is_preprint":false},{"year":2014,"finding":"sAC/ADCY10 is expressed in peripheral arterial chemoreceptors (carotid body), where HCO3- upregulates both sAC gene expression and cAMP levels, suggesting sAC functions as a CO2/HCO3- sensor regulating cAMP in chemoreceptor physiology.","method":"Quantitative real-time PCR for sAC mRNA, cAMP level measurement in tissues exposed to increasing HCO3- concentrations, comparison across chemosensitive and non-chemosensitive ganglia","journal":"Advances in experimental medicine and biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional cAMP assay plus expression data, single study","pmids":["19536486"],"is_preprint":false},{"year":2019,"finding":"A homozygous 2-bp frameshift deletion in ADCY10 (c.1205_1206del) 10 amino acids upstream of the nucleotide binding site causes severe asthenozoospermia in humans; treatment of patient sperm with cell-permeable cAMP analogs significantly rescued motility, directly implicating loss of sAC/ADCY10-generated cAMP as the pathogenic mechanism.","method":"Whole exome sequencing, Sanger sequencing, computer-assisted sperm analysis (CASA), cAMP analog rescue experiment in patient sperm","journal":"Human reproduction (Oxford, England)","confidence":"High","confidence_rationale":"Tier 2 — human loss-of-function variant with functional cAMP rescue, mechanistically linking ADCY10 to sperm motility","pmids":["31119281"],"is_preprint":false},{"year":2021,"finding":"ADCY10 acts as a key downstream effector of glutamate signaling in lung adenocarcinoma: accumulated endogenous glutamate activates ADCY10, which stimulates PKA-dependent phosphorylation and inhibition of GFPT1 (rate-limiting enzyme of the hexosamine biosynthesis pathway), thereby suppressing O-GlcNAcylation and stability of YAP, promoting ferroptosis sensitivity.","method":"Co-immunoprecipitation, luciferase reporter assay, ChIP, EMSA, immunoblotting, qPCR, metabolite measurement, cell viability/lipid ROS assays, CDX and PDX xenograft models, ADCY10 knockdown/overexpression","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (co-IP, ChIP, EMSA, reporter, in vivo models) establishing ADCY10 pathway position","pmids":["33897873"],"is_preprint":false},{"year":2021,"finding":"Pharmacological inhibition of sAC/ADCY10 with the potent inhibitor TDI-10229 (nanomolar potency in biochemical and cellular assays) is sufficient to interrogate sAC biology in vivo, validating sAC as a druggable enzyme whose catalytic inhibition blocks intracellular cAMP signaling.","method":"Biochemical adenylyl cyclase inhibition assay, cellular cAMP assay, mouse pharmacokinetic studies, medicinal chemistry optimization","journal":"ACS medicinal chemistry letters","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro enzymatic assay with cellular validation and in vivo PK, single lab","pmids":["34413957"],"is_preprint":false},{"year":2022,"finding":"Second-generation sAC/ADCY10 inhibitors with slow dissociation rates and high intrinsic potency were identified as required design elements for contraceptive applications, demonstrating that sustained enzymatic inhibition of sAC catalytic activity is mechanistically necessary to block sperm motility and acrosome reaction.","method":"In vitro sAC enzymatic inhibition assays (kinetics), cellular cAMP assays, sperm motility and acrosome reaction assays, medicinal chemistry structure-activity relationship","journal":"Journal of medicinal chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 — kinetic enzymatic characterization with cellular and sperm functional assays, single lab","pmids":["36346696"],"is_preprint":false},{"year":2014,"finding":"sAC/ADCY10 orthologs across aquatic animals are directly stimulated by HCO3- ions (the two catalytic domains are related to HCO3--regulated adenylyl cyclases from cyanobacteria), and sAC functions as a de facto CO2/pH sensor when associated with carbonic anhydrases, representing an evolutionarily conserved cAMP-based mechanism for sensing acid-base conditions.","method":"Comparative biochemistry, bioinformatics, and review of experimental studies (biochemical HCO3- stimulation assays, RT-PCR for ortholog expression, physiological studies in shark gills, fish intestine, sea urchin sperm)","journal":"The Journal of experimental biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — mechanistic inference from comparative biochemistry and multiple organism studies, review but cites primary experimental data","pmids":["24574382"],"is_preprint":false}],"current_model":"ADCY10 encodes soluble adenylyl cyclase (sAC), a bicarbonate-sensing enzyme that generates cAMP independently of G-protein regulation; in sperm it forms a flagellar signaling complex with sNHE, is activated by HCO3- (requiring extracellular Ca2+ and carbonic anhydrase activity), and drives cAMP-dependent PKA activation essential for capacitation, tyrosine phosphorylation, and motility, while in somatic cells (including lung adenocarcinoma) it acts downstream of glutamate to activate PKA, suppress GFPT1/HBP/YAP signaling, and modulate ferroptosis sensitivity."},"narrative":{"teleology":[{"year":2006,"claim":"Establishing that sAC is the essential cAMP source in sperm resolved the long-standing question of which adenylyl cyclase drives capacitation, placing a single bicarbonate-responsive enzyme at the center of sperm activation.","evidence":"sAC-knockout mouse spermatozoa analyzed by cAMP measurement, beat frequency, Ca²⁺ imaging, and tyrosine phosphorylation assays with cAMP-analog rescue","pmids":["16842770"],"confidence":"High","gaps":["How sAC is recruited to specific flagellar subdomains was not resolved","Whether somatic sAC isoforms share the same regulatory requirements was unknown"]},{"year":2007,"claim":"Identification of the sNHE–sAC flagellar complex and the requirement for extracellular Ca²⁺ upstream of sAC activation defined the signaling hierarchy (Ca²⁺ → HCO3⁻ entry → sAC → cAMP) that links extracellular cues to the cAMP cascade in sperm.","evidence":"Reciprocal co-immunoprecipitation in sNHE-null and wild-type sperm; Ca²⁺ removal/replacement and carbonic anhydrase inhibitor experiments with beat-frequency readout","pmids":["17517652","17950270"],"confidence":"High","gaps":["Direct structural basis for the sNHE–sAC interaction is unknown","Mechanism by which Ca²⁺ facilitates HCO3⁻-dependent sAC activation was not determined"]},{"year":2008,"claim":"Discovery of an alternative somatic sAC isoform using a distinct transcriptional start site explained why the original knockout lacked somatic phenotypes and revealed underappreciated locus complexity.","evidence":"RT-PCR and western blot isoform mapping in somatic tissues of Sacytm1Lex knockout mice","pmids":["18806876"],"confidence":"High","gaps":["Functional differences between somatic and full-length sAC isoforms remain uncharacterized","Whether the somatic isoform retains full HCO3⁻ sensitivity is untested"]},{"year":2014,"claim":"Demonstration that sAC orthologs across metazoans are directly stimulated by HCO3⁻ and function as CO2/pH sensors when coupled to carbonic anhydrases established an evolutionarily conserved acid–base sensing paradigm for this cyclase family.","evidence":"Comparative biochemistry and bioinformatic analysis of catalytic domains across cyanobacteria, aquatic vertebrates, and mammals; HCO3⁻ stimulation assays in shark gill and sea urchin sperm","pmids":["24574382","19536486"],"confidence":"Medium","gaps":["Structural basis for HCO3⁻ binding at the catalytic site has not been resolved at atomic resolution","In vivo chemoreceptor studies remain limited to expression and cAMP correlations"]},{"year":2019,"claim":"Identification of a homozygous loss-of-function ADCY10 mutation causing human asthenozoospermia, rescuable by exogenous cAMP, translated the mouse findings to human pathology and validated sAC-generated cAMP as the critical determinant of human sperm motility.","evidence":"Whole-exome and Sanger sequencing of infertile patient; CASA motility analysis with cAMP-analog rescue","pmids":["31119281"],"confidence":"High","gaps":["Only a single family was reported; additional human alleles are needed to generalize genotype–phenotype correlation","Whether the truncated protein retains any partial activity was not tested"]},{"year":2021,"claim":"Positioning sAC downstream of glutamate and upstream of PKA–GFPT1–YAP in lung adenocarcinoma revealed a somatic tumor-suppressive role for sAC that connects metabolic signaling to ferroptosis sensitivity, extending sAC biology far beyond reproductive physiology.","evidence":"Co-IP, ChIP, EMSA, reporter assays, lipid ROS and cell viability assays, CDX and PDX xenograft models with ADCY10 knockdown/overexpression","pmids":["33897873"],"confidence":"High","gaps":["Whether HCO3⁻ sensing is relevant for sAC activation in this tumor context is unknown","Generalizability to other cancer types has not been assessed"]},{"year":2022,"claim":"Development of potent, slow-dissociating sAC inhibitors validated the enzyme as a druggable target and demonstrated that sustained catalytic blockade is required to abolish sperm motility, informing a non-hormonal male contraceptive strategy.","evidence":"Biochemical kinetic assays, cellular cAMP assays, sperm motility and acrosome reaction assays, in vivo mouse PK","pmids":["34413957","36346696"],"confidence":"Medium","gaps":["In vivo contraceptive efficacy in mating trials has not been reported","Off-target effects of sAC inhibitors on somatic cAMP pools require systematic evaluation"]},{"year":null,"claim":"Key unresolved questions include the atomic-resolution mechanism of HCO3⁻ activation, functional specialization of somatic versus full-length sAC isoforms, and in vivo validation of sAC inhibitors as contraceptives.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution co-crystal structure of sAC with HCO3⁻ has been reported","Somatic isoform-specific knockouts have not been generated","In vivo contraceptive efficacy data are lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0009975","term_label":"cyclase activity","supporting_discovery_ids":[0,2,4,9]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[2,4,9]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,6]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[6]}],"complexes":["sNHE-sAC flagellar signaling complex"],"partners":["SLC9C1","GFPT1","PRKACA"],"other_free_text":[]},"mechanistic_narrative":"ADCY10 encodes soluble adenylyl cyclase (sAC), a bicarbonate-responsive cyclase that generates cAMP independently of heterotrimeric G-protein signaling, functioning as an evolutionarily conserved intracellular CO2/HCO3⁻/pH sensor [PMID:24574382]. In spermatozoa, sAC is the predominant adenylyl cyclase and forms a flagellar signaling complex with the sperm-specific Na⁺/H⁺ exchanger (sNHE); HCO3⁻ stimulation—requiring extracellular Ca²⁺ and carbonic anhydrase activity—activates sAC to produce cAMP that drives PKA-dependent capacitation, tyrosine phosphorylation, hyperactivated motility, and the acrosome reaction [PMID:16842770, PMID:17517652, PMID:17950270]. Loss-of-function mutations in human ADCY10 cause severe asthenozoospermia rescuable by cell-permeable cAMP analogs [PMID:31119281]. In somatic cells, including lung adenocarcinoma, sAC transduces glutamate signals to activate PKA, which phosphorylates GFPT1 to suppress the hexosamine biosynthesis pathway and destabilize YAP, thereby modulating ferroptosis sensitivity [PMID:33897873]."},"prefetch_data":{"uniprot":{"accession":"Q96PN6","full_name":"Adenylate cyclase type 10","aliases":["AH-related protein","Adenylate cyclase homolog","Germ cell soluble adenylyl cyclase","hsAC","sAC","Testicular soluble adenylyl cyclase"],"length_aa":1610,"mass_kda":187.1,"function":"Catalyzes the formation of the signaling molecule cAMP (PubMed:12609998, PubMed:15659711, PubMed:24567411, PubMed:24616449, PubMed:25040695). May function as sensor that mediates responses to changes in cellular bicarbonate and CO(2) levels (PubMed:15659711, PubMed:17591988). Has a critical role in mammalian spermatogenesis by producing the cAMP which regulates cAMP-responsive nuclear factors indispensable for sperm maturation in the epididymis. Induces capacitation, the maturational process that sperm undergo prior to fertilization (By similarity). Involved in ciliary beat regulation (PubMed:17591988)","subcellular_location":"Cell membrane; Cytoplasm, cytoskeleton; Cytoplasm, perinuclear region; Nucleus; Cell projection, cilium; Cytoplasm; Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q96PN6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADCY10","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ADCY10","total_profiled":1310},"omim":[{"mim_id":"621459","title":"TRANSMEMBRANE PROTEIN 217; TMEM217","url":"https://www.omim.org/entry/621459"},{"mim_id":"612738","title":"SOLUTE CARRIER FAMILY 9, MEMBER C1; SLC9C1","url":"https://www.omim.org/entry/612738"},{"mim_id":"605205","title":"ADENYLATE CYCLASE 10; ADCY10","url":"https://www.omim.org/entry/605205"},{"mim_id":"143870","title":"HYPERCALCIURIA, ABSORPTIVE, 2; HCA2","url":"https://www.omim.org/entry/143870"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"liver","ntpm":5.7},{"tissue":"testis","ntpm":16.4}],"url":"https://www.proteinatlas.org/search/ADCY10"},"hgnc":{"alias_symbol":["SAC","Sacy","SACI","HCA2","RP1-313L4.2"],"prev_symbol":[]},"alphafold":{"accession":"Q96PN6","domains":[{"cath_id":"-","chopping":"2-31_248-270","consensus_level":"medium","plddt":80.1109,"start":2,"end":270},{"cath_id":"3.30.70.1230","chopping":"35-239","consensus_level":"high","plddt":85.0709,"start":35,"end":239},{"cath_id":"3.30.70.1230","chopping":"282-463","consensus_level":"high","plddt":86.5541,"start":282,"end":463},{"cath_id":"3.40.50.300","chopping":"490-625_638-698","consensus_level":"high","plddt":86.2612,"start":490,"end":698},{"cath_id":"-","chopping":"700-758_767-781_790-806","consensus_level":"medium","plddt":72.434,"start":700,"end":806},{"cath_id":"-","chopping":"809-899_911-961","consensus_level":"medium","plddt":76.5151,"start":809,"end":961},{"cath_id":"1.25.40","chopping":"972-985_1058-1163","consensus_level":"medium","plddt":86.6647,"start":972,"end":1163},{"cath_id":"1.25.40,1.25.40","chopping":"1389-1598","consensus_level":"medium","plddt":86.1833,"start":1389,"end":1598}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PN6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PN6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96PN6-F1-predicted_aligned_error_v6.png","plddt_mean":81.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADCY10","jax_strain_url":"https://www.jax.org/strain/search?query=ADCY10"},"sequence":{"accession":"Q96PN6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96PN6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96PN6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96PN6"}},"corpus_meta":[{"pmid":"24626186","id":"PMC_24626186","title":"Partial 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sAC-null sperm have greatly diminished adenylyl cyclase activity and cAMP content, fail to respond to HCO3- stimulation (flagellar beat frequency, Ca2+ entry), and do not develop hyperactivated motility or capacitation-associated tyrosine phosphorylation, establishing sAC as essential for cAMP-dependent sperm capacitation and motility.\",\n      \"method\": \"sAC knockout mouse model (sAC-/- spermatozoa), adenylyl cyclase activity assays, cAMP measurement, Ca2+ imaging, flagellar beat frequency analysis, protein tyrosine phosphorylation assays, rescue with cell-permeable cAMP analogs\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods in KO model with specific phenotypic readouts, replicated across assays\",\n      \"pmids\": [\"16842770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The sperm-specific Na+/H+ exchanger (sNHE) physically associates with sAC/ADCY10 at the sperm flagellar plasma membrane (co-immunoprecipitation and codependent expression), and sNHE is required for full-length sAC expression and for bicarbonate-stimulated sAC activity in spermatozoa, placing sNHE and sAC in the same flagellar signaling complex.\",\n      \"method\": \"Co-immunoprecipitation, sNHE-null mouse model, western blotting, adenylyl cyclase activity assay, cAMP-dependent tyrosine phosphorylation assay, motility rescue with cell-permeable cAMP analogs\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus KO model with multiple orthogonal readouts\",\n      \"pmids\": [\"17517652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"External Ca2+ is required upstream of sAC/ADCY10 (SACY) for HCO3--evoked cAMP elevation and motility activation in sperm; Ca2+ is not needed for cAMP-AM to increase beat frequency, placing extracellular Ca2+ between HCO3- stimulus and sAC activation. Carbonic anhydrase activity also facilitates rapid HCO3- action on sAC.\",\n      \"method\": \"Ca2+ removal/replacement experiments, caged-Ca2+ photolysis, carbonic anhydrase inhibitor (acetazolamide), cAMP-AM rescue, flagellar beat frequency measurement\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — pharmacological dissection with multiple orthogonal interventions definitively ordering Ca2+ upstream of sAC\",\n      \"pmids\": [\"17950270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Somatic tissues express a previously uncharacterized isoform of sAC/ADCY10 that uses a unique transcriptional start site and escapes deletion of exons 2-4 present in the Sacytm1Lex knockout allele, explaining the absence of somatic phenotype in that mouse line and demonstrating increased complexity at the ADCY10 locus.\",\n      \"method\": \"Immunological (western blot) and molecular biological (RT-PCR, isoform mapping) characterization of somatic tissues from Sacytm1Lex/Sacytm1Lex knockout mice\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal molecular methods identifying novel isoform in KO model\",\n      \"pmids\": [\"18806876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"sAC/ADCY10 is expressed in peripheral arterial chemoreceptors (carotid body), where HCO3- upregulates both sAC gene expression and cAMP levels, suggesting sAC functions as a CO2/HCO3- sensor regulating cAMP in chemoreceptor physiology.\",\n      \"method\": \"Quantitative real-time PCR for sAC mRNA, cAMP level measurement in tissues exposed to increasing HCO3- concentrations, comparison across chemosensitive and non-chemosensitive ganglia\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional cAMP assay plus expression data, single study\",\n      \"pmids\": [\"19536486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A homozygous 2-bp frameshift deletion in ADCY10 (c.1205_1206del) 10 amino acids upstream of the nucleotide binding site causes severe asthenozoospermia in humans; treatment of patient sperm with cell-permeable cAMP analogs significantly rescued motility, directly implicating loss of sAC/ADCY10-generated cAMP as the pathogenic mechanism.\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing, computer-assisted sperm analysis (CASA), cAMP analog rescue experiment in patient sperm\",\n      \"journal\": \"Human reproduction (Oxford, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human loss-of-function variant with functional cAMP rescue, mechanistically linking ADCY10 to sperm motility\",\n      \"pmids\": [\"31119281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADCY10 acts as a key downstream effector of glutamate signaling in lung adenocarcinoma: accumulated endogenous glutamate activates ADCY10, which stimulates PKA-dependent phosphorylation and inhibition of GFPT1 (rate-limiting enzyme of the hexosamine biosynthesis pathway), thereby suppressing O-GlcNAcylation and stability of YAP, promoting ferroptosis sensitivity.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay, ChIP, EMSA, immunoblotting, qPCR, metabolite measurement, cell viability/lipid ROS assays, CDX and PDX xenograft models, ADCY10 knockdown/overexpression\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (co-IP, ChIP, EMSA, reporter, in vivo models) establishing ADCY10 pathway position\",\n      \"pmids\": [\"33897873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pharmacological inhibition of sAC/ADCY10 with the potent inhibitor TDI-10229 (nanomolar potency in biochemical and cellular assays) is sufficient to interrogate sAC biology in vivo, validating sAC as a druggable enzyme whose catalytic inhibition blocks intracellular cAMP signaling.\",\n      \"method\": \"Biochemical adenylyl cyclase inhibition assay, cellular cAMP assay, mouse pharmacokinetic studies, medicinal chemistry optimization\",\n      \"journal\": \"ACS medicinal chemistry letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro enzymatic assay with cellular validation and in vivo PK, single lab\",\n      \"pmids\": [\"34413957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Second-generation sAC/ADCY10 inhibitors with slow dissociation rates and high intrinsic potency were identified as required design elements for contraceptive applications, demonstrating that sustained enzymatic inhibition of sAC catalytic activity is mechanistically necessary to block sperm motility and acrosome reaction.\",\n      \"method\": \"In vitro sAC enzymatic inhibition assays (kinetics), cellular cAMP assays, sperm motility and acrosome reaction assays, medicinal chemistry structure-activity relationship\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — kinetic enzymatic characterization with cellular and sperm functional assays, single lab\",\n      \"pmids\": [\"36346696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"sAC/ADCY10 orthologs across aquatic animals are directly stimulated by HCO3- ions (the two catalytic domains are related to HCO3--regulated adenylyl cyclases from cyanobacteria), and sAC functions as a de facto CO2/pH sensor when associated with carbonic anhydrases, representing an evolutionarily conserved cAMP-based mechanism for sensing acid-base conditions.\",\n      \"method\": \"Comparative biochemistry, bioinformatics, and review of experimental studies (biochemical HCO3- stimulation assays, RT-PCR for ortholog expression, physiological studies in shark gills, fish intestine, sea urchin sperm)\",\n      \"journal\": \"The Journal of experimental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — mechanistic inference from comparative biochemistry and multiple organism studies, review but cites primary experimental data\",\n      \"pmids\": [\"24574382\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADCY10 encodes soluble adenylyl cyclase (sAC), a bicarbonate-sensing enzyme that generates cAMP independently of G-protein regulation; in sperm it forms a flagellar signaling complex with sNHE, is activated by HCO3- (requiring extracellular Ca2+ and carbonic anhydrase activity), and drives cAMP-dependent PKA activation essential for capacitation, tyrosine phosphorylation, and motility, while in somatic cells (including lung adenocarcinoma) it acts downstream of glutamate to activate PKA, suppress GFPT1/HBP/YAP signaling, and modulate ferroptosis sensitivity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ADCY10 encodes soluble adenylyl cyclase (sAC), a bicarbonate-responsive cyclase that generates cAMP independently of heterotrimeric G-protein signaling, functioning as an evolutionarily conserved intracellular CO2/HCO3⁻/pH sensor [PMID:24574382]. In spermatozoa, sAC is the predominant adenylyl cyclase and forms a flagellar signaling complex with the sperm-specific Na⁺/H⁺ exchanger (sNHE); HCO3⁻ stimulation—requiring extracellular Ca²⁺ and carbonic anhydrase activity—activates sAC to produce cAMP that drives PKA-dependent capacitation, tyrosine phosphorylation, hyperactivated motility, and the acrosome reaction [PMID:16842770, PMID:17517652, PMID:17950270]. Loss-of-function mutations in human ADCY10 cause severe asthenozoospermia rescuable by cell-permeable cAMP analogs [PMID:31119281]. In somatic cells, including lung adenocarcinoma, sAC transduces glutamate signals to activate PKA, which phosphorylates GFPT1 to suppress the hexosamine biosynthesis pathway and destabilize YAP, thereby modulating ferroptosis sensitivity [PMID:33897873].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Establishing that sAC is the essential cAMP source in sperm resolved the long-standing question of which adenylyl cyclase drives capacitation, placing a single bicarbonate-responsive enzyme at the center of sperm activation.\",\n      \"evidence\": \"sAC-knockout mouse spermatozoa analyzed by cAMP measurement, beat frequency, Ca²⁺ imaging, and tyrosine phosphorylation assays with cAMP-analog rescue\",\n      \"pmids\": [\"16842770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How sAC is recruited to specific flagellar subdomains was not resolved\",\n        \"Whether somatic sAC isoforms share the same regulatory requirements was unknown\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of the sNHE–sAC flagellar complex and the requirement for extracellular Ca²⁺ upstream of sAC activation defined the signaling hierarchy (Ca²⁺ → HCO3⁻ entry → sAC → cAMP) that links extracellular cues to the cAMP cascade in sperm.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation in sNHE-null and wild-type sperm; Ca²⁺ removal/replacement and carbonic anhydrase inhibitor experiments with beat-frequency readout\",\n      \"pmids\": [\"17517652\", \"17950270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct structural basis for the sNHE–sAC interaction is unknown\",\n        \"Mechanism by which Ca²⁺ facilitates HCO3⁻-dependent sAC activation was not determined\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery of an alternative somatic sAC isoform using a distinct transcriptional start site explained why the original knockout lacked somatic phenotypes and revealed underappreciated locus complexity.\",\n      \"evidence\": \"RT-PCR and western blot isoform mapping in somatic tissues of Sacytm1Lex knockout mice\",\n      \"pmids\": [\"18806876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional differences between somatic and full-length sAC isoforms remain uncharacterized\",\n        \"Whether the somatic isoform retains full HCO3⁻ sensitivity is untested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstration that sAC orthologs across metazoans are directly stimulated by HCO3⁻ and function as CO2/pH sensors when coupled to carbonic anhydrases established an evolutionarily conserved acid–base sensing paradigm for this cyclase family.\",\n      \"evidence\": \"Comparative biochemistry and bioinformatic analysis of catalytic domains across cyanobacteria, aquatic vertebrates, and mammals; HCO3⁻ stimulation assays in shark gill and sea urchin sperm\",\n      \"pmids\": [\"24574382\", \"19536486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis for HCO3⁻ binding at the catalytic site has not been resolved at atomic resolution\",\n        \"In vivo chemoreceptor studies remain limited to expression and cAMP correlations\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of a homozygous loss-of-function ADCY10 mutation causing human asthenozoospermia, rescuable by exogenous cAMP, translated the mouse findings to human pathology and validated sAC-generated cAMP as the critical determinant of human sperm motility.\",\n      \"evidence\": \"Whole-exome and Sanger sequencing of infertile patient; CASA motility analysis with cAMP-analog rescue\",\n      \"pmids\": [\"31119281\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Only a single family was reported; additional human alleles are needed to generalize genotype–phenotype correlation\",\n        \"Whether the truncated protein retains any partial activity was not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Positioning sAC downstream of glutamate and upstream of PKA–GFPT1–YAP in lung adenocarcinoma revealed a somatic tumor-suppressive role for sAC that connects metabolic signaling to ferroptosis sensitivity, extending sAC biology far beyond reproductive physiology.\",\n      \"evidence\": \"Co-IP, ChIP, EMSA, reporter assays, lipid ROS and cell viability assays, CDX and PDX xenograft models with ADCY10 knockdown/overexpression\",\n      \"pmids\": [\"33897873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether HCO3⁻ sensing is relevant for sAC activation in this tumor context is unknown\",\n        \"Generalizability to other cancer types has not been assessed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Development of potent, slow-dissociating sAC inhibitors validated the enzyme as a druggable target and demonstrated that sustained catalytic blockade is required to abolish sperm motility, informing a non-hormonal male contraceptive strategy.\",\n      \"evidence\": \"Biochemical kinetic assays, cellular cAMP assays, sperm motility and acrosome reaction assays, in vivo mouse PK\",\n      \"pmids\": [\"34413957\", \"36346696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo contraceptive efficacy in mating trials has not been reported\",\n        \"Off-target effects of sAC inhibitors on somatic cAMP pools require systematic evaluation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic-resolution mechanism of HCO3⁻ activation, functional specialization of somatic versus full-length sAC isoforms, and in vivo validation of sAC inhibitors as contraceptives.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution co-crystal structure of sAC with HCO3⁻ has been reported\",\n        \"Somatic isoform-specific knockouts have not been generated\",\n        \"In vivo contraceptive efficacy data are lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0009975\", \"supporting_discovery_ids\": [0, 2, 4, 9]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [2, 4, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 6]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\n      \"sNHE-sAC flagellar signaling complex\"\n    ],\n    \"partners\": [\n      \"SLC9C1\",\n      \"GFPT1\",\n      \"PRKACA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}