Soluble adenylyl cyclase isoforms essential for male fertility

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DESCRIPTION (provided by applicant): The ubiquitous second messenger, cAMP, plays multiple roles in male germ cells critical for mammalian fertilization. The major source of cAMP in sperm is the bicarbonate and calcium regulated soluble adenylyl cyclase (sAC). In testis, alternative splicing produces two isoforms, sACt and sACfl, and their deletion (in Sacytm1Lex knockout mice) or inhibition (by small molecule, sAC-specific inhibitor) blocks sperm motility, capacitation, and in vitro fertilization. Since both sACt and sACfl are removed in the Sacytm1Lex knockout and inhibited by the small molecule inhibitor, their individual contributions to the multiple sAC-derived cAMP-dependent processes in sperm remains unclear. In this application, we propose immunological, biochemical, and genetic experiments to determine whether there is a functional necessity for multiple sAC splice variants and to distinguish their individual roles in testis and male germ cells. These studies may justify sAC to be target for contraceptive intervention. The studies proposed here may reveal unique aspects to the regulation of sperm cAMP signal transduction which could define a new target for contraceptive intervention. PUBLIC HEALTH RELEVANCE: The studies proposed here may reveal unique aspects to the regulation of sperm cAMP signal transduction which could define a new target for contraceptive intervention.