The “Soluble” Adenylyl Cyclase in Sperm Mediates Multiple Signaling Events Required for Fertilization

Abstract

Mammalian fertilization is dependent upon a series of bicarbonate-induced, cAMP-dependent processes sperm undergo as they "capacitate," i.e., acquire the ability to fertilize eggs. Male mice lacking the bicarbonate- and calcium-responsive soluble adenylyl cyclase (sAC), the predominant source of cAMP in male germ cells, are infertile, as the sperm are immotile. Membrane-permeable cAMP analogs are reported to rescue the motility defect, but we now show that these "rescued" null sperm were not hyperactive, displayed flagellar angulation, and remained unable to fertilize eggs in vitro. These deficits uncover a requirement for sAC during spermatogenesis and/or epididymal maturation and reveal limitations inherent in studying sAC function using knockout mice. To circumvent this restriction, we identified a specific sAC inhibitor that allowed temporal control over sAC activity. This inhibitor revealed that capacitation is defined by separable events: induction of protein tyrosine phosphorylation and motility are sAC dependent while acrosomal exocytosis is not dependent on sAC.

Moving to the beat: a review of mammalian sperm motility regulation

“…One mechanism by which calcium is directly linked to flagellar function is through its regulation of the atypical 'soluble' adenylyl cyclase (sAC), which generates cAMP to activate PKA. The sAC is required for sperm motility and is molecularly and biochemically distinct from the transmembrane adenylyl cyclases (tmACs), in part because sAC is uniquely sensitive to both bicarbonate and calcium (Buck et al 1999;Chen et al 2000;Wuttke et al 2001;Jaiswal and Conti 2003;Litvin et al 2003;Esposito et al 2004;Liguori et al 2004;Hess et al 2005). Thus, through sAC, calcium signalling can be linked to PKA signalling as parts of a single pathway.…”

“…Interestingly, the effects of calcium on sAC are independent of CaM (Jaiswal and Conti 2003;Litvin et al 2003). Therefore, although it is known that sAC is required for sperm motility (Esposito et al 2004;Hess et al 2005), and although sAC is regulated by Ca, the effect of CaM on motility is not achieved via this cyclase.…”

Protein biomarkers for male artificial insemination subfertility in bovine spermatozoa

“…A soluble type of adenylyl cyclase, “ADCY10,”94, 95, 96, 97, 98 is unique in its lack of transmembrane domains, independence of G‐protein‐coupled receptors, and direct stimulation by the interaction with bicarbonate and Ca 2+ , compared with the transmembrane types of the adenylyl cyclase, “ADCY1‐9.” This isoform is synthesized most abundantly in mouse testes as either the 189 kDa full‐length form or the 48 kDa truncated form from the same Adcy10 gene by alternative splicing. Although both forms contain two cyclase domains that catalyze the conversion from ATP to cAMP, the specific activity of the truncated form is 20‐fold higher than that of the full‐length form.…”

Cl− Channels and Transporters in Sperm Physiology

“…The stimulation of the sperm soluble adenylate cyclase by HCO 3 − and the consequent cAMP/PKA stimulation is required for the activated motility (Carlson et al 2007 ;Esposito et al 2004 ;Hess et al 2005 ;Nolan et al 2004 ;Xie et al 2006 ). After some time (varying according to species) in the female tract, spermatozoa become hyperactivated, displaying vigorous asymmetrical fl agellar beating with large amplitude and high curvature.…”

“…HCO 3 − regulation is particularly important in spermatozoa because it activates cAMP synthesis by the atypical soluble adenylyl cyclase present in these cells (Hess et al 2005 ;Okamura et al 1985 ). The specifi c carriers responsible for HCO 3 − transport have not yet been fully defi ned.…”