Mice deficient for soluble adenylyl cyclase are infertile because of a severe sperm-motility defect

Abstract

To acquire the ability to fertilize, spermatozoa undergo complex, but at present poorly understood, activation processes. The intracellular rise of cAMP produced by the bicarbonate-dependent soluble adenylyl cyclase (sAC) has been suggested to play a central role in initiating the cascade of the events that culminates in spermatozoa maturation. Here, we show that targeted disruption of the sAC gene does not affect spermatogenesis but dramatically impairs sperm motility, leading to male sterility. sAC mutant spermatozoa are characterized by a total loss of forward motility and are unable to fertilize oocytes in vitro. Interestingly, motility in sAC mutant spermatozoa can be restored on cAMP loading, indicating that the motility defect observed is not caused by a structural defect. We, therefore, conclude that sAC plays an essential and nonredundant role in the activation of the signaling cascade controlling motility and, therefore, in fertility. The crucial role of sAC in fertility and the absence of any other obvious pathological abnormalities in sAC-deficient mice may provide a rationale for developing inhibitors that can be applied as a human male contraceptive

A soluble adenylyl cyclase from sea urchin spermatozoa

“…Gene knockouts of the sAC result in normal male mice with sperm that are immotile and thus sterile. The immotile sperm become motile when exposed to permeable analogs of cAMP [29]. These data are proof that sAC is involved in generating the cAMP required for motility.…”

Phosphodiesterase 11 (PDE11) regulation of spermatozoa physiology

“…Knockout male mice with targeted disruption of CatSper (CatSper À/À ) or sAC (sAC À/À ) have similar appearance, mounting behavior and sperm concentration as PDE11 þ / þ littermates, but are completely sterile due to an inability to activate capacitance. 29,33 Sperm from CatSper À/À and sAC À/À mice have severely impaired motility and complete lack of forward progression, and are unable to fertilize intact eggs or zona pellucida null eggs in vitro. Moreover, the mAC-specific inhibitor, SQ22536, prevented spermatozoan Ca 2 þ signaling, chemotaxis and hyperactivation.…”

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.…”