Soluble adenylyl cyclase inhibition prevents human sperm functions essential for fertilization.

TitleSoluble adenylyl cyclase inhibition prevents human sperm functions essential for fertilization.
Publication TypeJournal Article
Year of Publication2021
AuthorsBalbach M, Ghanem L, Rossetti T, Kaur N, Ritagliati C, Ferreira J, Krapf D, Molina LCPuga, Santi CMaria, Hansen JNiklas, Wachten D, Fushimi M, Meinke PT, Buck J, Levin LR
JournalMol Hum Reprod
Volume27
Issue9
Date Published2021 Sep 01
ISSN1460-2407
KeywordsAdenylyl Cyclase Inhibitors, Adenylyl Cyclases, Animals, Cells, Cultured, Female, Fertilization, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Inbred ICR, Mice, Knockout, Pregnancy, Spermatozoa
Abstract

Soluble adenylyl cyclase (sAC: ADCY10) has been genetically confirmed to be essential for male fertility in mice and humans. In mice, ex vivo studies of dormant, caudal epididymal sperm demonstrated that sAC is required for initiating capacitation and activating motility. We now use an improved sAC inhibitor, TDI-10229, for a comprehensive analysis of sAC function in mouse and human sperm. In contrast to caudal epididymal mouse sperm, human sperm are collected post-ejaculation, after sAC activity has already been stimulated. In addition to preventing the capacitation-induced stimulation of sAC and protein kinase A activities, tyrosine phosphorylation, alkalinization, beat frequency and acrosome reaction in dormant mouse sperm, sAC inhibitors interrupt each of these capacitation-induced changes in ejaculated human sperm. Furthermore, we show for the first time that sAC is required during acrosomal exocytosis in mouse and human sperm. These data define sAC inhibitors as candidates for non-hormonal, on-demand contraceptives suitable for delivery via intravaginal devices in women.

DOI10.1093/molehr/gaab054
Alternate JournalMol Hum Reprod
PubMed ID34463764
PubMed Central IDPMC8473925
Grant ListT32 GM073546 / GM / NIGMS NIH HHS / United States
F31 AG069501 / AG / NIA NIH HHS / United States
R01 HD088571 / HD / NICHD NIH HHS / United States
R01 HD069631 / HD / NICHD NIH HHS / United States
F31 HD105363 / HD / NICHD NIH HHS / United States
P50 HD100549 / HD / NICHD NIH HHS / United States