The cAMP/PKA signaling pathway is used in mammals to regulate gene transcription. In fact, sperm capacitation is a cAMP-dependent process that up regulates the Ca
2+ concentration and tyrosine phosphorylation levels [
52]. Cyclic AMP is synthesized by many types of adenylyl cyclases (ACs) that are commonly divided into two groups: transmembrane adenylyl cyclases (tmACs) and sAC [
19]. Importantly, sAC-mediated cAMP/PKA signal cascades are essential for sperm capacitation, because sAC-mutant or sAC-null mice can produce sperm, but sperm exhibit no forward motility, causing male infertility. Giving cAMP analogs to sAC-mutant or sAC-null mice completely restores the previously lost motility, but the sperm still exhibit no hyperactivity to fertilize eggs in vitro [
53,
54]. Moreover, sAC not only plays a role in producting cAMP but also participates in other mechanisms involved in the fertilization process. Specifically, sAC have three roles in fertilization. First, sAC works as a HCO
3
− sensor. The structural domains of sAC rearrange after being stimulating by HCO
3
−, and sAC is activated by increasing cAMP levels in sperm [
54,
55]. The second function of sAC is to act as a pH sensor. Previous work showed that sAC regulate acid/base equilibrium in dogfish sperm [
56], and its gene works as a monitor which reflects the concentration of CO
2 and HCO
3
− to keep an appropriate pH microenvironment [
55]. The last function of sAC is to function as a Ca
2+ sensor or calmodulin. As a substitute for HCO
3
−, Ca
2+ can stimulate a combination of sAC with ATP to produce cAMP [
57,
58]. Cyclic AMP is a second messenger molecule that is integral to many physiological processes, including sperm chemotaxis towards to the egg and capacitation. A study showed that extracellular cAMP/cGMP increases the Ca
2+ concentration [
59]. When providing 8-Br-cAMP/cGMP to the spermatophore or providing alkaline depolarization to activate the spermatophore, a Catsper-dependent increase in the intracellular Ca
2+ concentration initiates at the principal piece and speads through the midpiece to finally reach the head. This process occurs in a matter of seconds. Furthermore, compared with wild-type sperm, Catsper1-mutant sperm have lower intracellular ATP levels [
59]. In addition, cGMP signalling function in marine invertebrates to transducer chemoattractants to increase in the [Ca
2+]i in the flagellum, thereby increases swimming behavior during chemotaxis [
60,
61]. All of these findings suggest that cyclic nucleotides induce Ca
2+ influx in the principal piece, but there is no clear evidence showing that this cyclic nucleotide-mediated process directly participates in inducing [Ca
2+]i increases. However, by using cells treated with 8-Br-cNMP, one study has demonstrated that a cyclic nucleotides modulates progesterone to ultimately increase [Ca
2+]i [
62].