title: Soluble adenylyl cyclase (sAC) is indispensable for sperm function and fertilization.
abstract: We previously demonstrated that male mice deficient in the soluble adenylyl cyclase (sAC) are sterile and produce spermatozoa with deficits in progressive motility and are unable to fertilize zona-intact eggs. Here, analyses of sAC(-/-) spermatozoa provide additional insights into the functions linked to cAMP signaling. Adenylyl cyclase activity and cAMP content are greatly diminished in crude preparations of sAC(-/-) spermatozoa and are undetectable after sperm purification. HCO(3)(-) is unable to rapidly accelerate the flagellar beat or facilitate evoked Ca(2+) entry into sAC(-/-) spermatozoa. Moreover, the delayed HCO(3)(-)-dependent increases in protein tyrosine phosphorylation and hyperactivated motility, which occur late in capacitation of wild-type spermatozoa, do not develop in sAC(-/-) spermatozoa. However, sAC(-/-) sperm fertilize zona-free oocytes, indicating that gamete fusion does not require sAC. Although ATP levels are significantly reduced in sAC(-/-) sperm, cAMP-AM ester increases flagellar beat frequency, progressive motility, and alters the pattern of tyrosine phosphorylated proteins. These results indicate that sAC and cAMP coordinate cellular energy balance in wild-type sperm and that the ATP generating machinery is not operating normally in sAC(-/-) spermatozoa. These findings demonstrate that sAC plays a critical role in cAMP signaling in spermatozoa and that defective cAMP production prevents engagement of multiple components of capacitation resulting in male infertility.
authors.affiliation: Division of Reproductive Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Garcia
authors.forename: Anne E
authors.initials: AE
authors.lastname: Carlson
authors.forename: Sonya M
authors.initials: SM
authors.lastname: Schuh
authors.forename: Donner F
authors.initials: DF
authors.lastname: Babcock
authors.forename: Bijay S
authors.initials: BS
authors.lastname: Jaiswal
authors.forename: Jan A
authors.initials: JA
authors.lastname: Gossen
authors.forename: Gloria
authors.initials: G
authors.lastname: Esposito
authors.forename: Marcel
authors.initials: M
authors.lastname: van Duin
authors.forename: Marco
authors.initials: M
authors.lastname: Conti
mesh_terms: D000262:Adenylyl Cyclases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D005306:Fertilization / Q000235:genetics / Q000502:physiology*; D007248:Infertility, Male / Q000201:enzymology / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D012995:Solubility; D013075:Sperm Capacitation / Q000235:genetics; D013094:Spermatozoa / Q000201:enzymology / Q000502:physiology*
chemical_list: D000242:Cyclic AMP; D000262:Adenylyl Cyclases