ADCY10

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).

1. 2006 High

   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

   PMID:16842770

   Open questions at the time

   • How sAC is recruited to specific flagellar subdomains was not resolved
   • Whether somatic sAC isoforms share the same regulatory requirements was unknown
2. 2007 High

   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

   PMID:17517652 PMID:17950270

   Open questions at the time

   • Direct structural basis for the sNHE–sAC interaction is unknown
   • Mechanism by which Ca²⁺ facilitates HCO3⁻-dependent sAC activation was not determined
3. 2008 High

   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

   PMID:18806876

   Open questions at the time

   • Functional differences between somatic and full-length sAC isoforms remain uncharacterized
   • Whether the somatic isoform retains full HCO3⁻ sensitivity is untested
4. 2014 Medium

   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

   PMID:19536486 PMID:24574382

   Open questions at the time

   • 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
5. 2019 High

   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

   PMID:31119281

   Open questions at the time

   • 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
6. 2021 High

   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

   PMID:33897873

   Open questions at the time

   • Whether HCO3⁻ sensing is relevant for sAC activation in this tumor context is unknown
   • Generalizability to other cancer types has not been assessed
7. 2022 Medium

   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

   PMID:34413957 PMID:36346696

   Open questions at the time

   • In vivo contraceptive efficacy in mating trials has not been reported
   • Off-target effects of sAC inhibitors on somatic cAMP pools require systematic evaluation

• 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.
• 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