Calcium Influx and Male Fertility in the Context of the Sperm Proteome: An Update
Figure 2
Schematic diagram showing the mechanism of Ca2+ regulated hyperactivation, capacitation, and the acrosome reaction of spermatozoa, which are three principal events of fertilization. Ca2+ together with ZP3 (zona pellucida glycoprotein-3) exhibits the most important role in sperm binding and acrosomal reaction. Ca2+ triggers the zona pellucida (ZP) receptors of cell membrane that activate G-proteins in the sperm head. Activated G-proteins stimulate the H+ transporter to increase intracellular pH, ultimately inducing the acrosomal reaction and hyperactivation by catalyzing the acrosomal enzymes [91]. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are produced from adenosine triphosphate (ATP) owing to enzymatic catalysis by soluble adenylate cyclase (sAC) and guanylate cyclase (sGC), respectively, in mature spermatozoa. The bicarbonate ions activate the sAC; however, follicular fluid also stimulates the sAC through release of Ca2+ ions via the CatSper channel (principal piece). However, G-protein mediated signal transduction activates sAC and phospholipase-C (PLC) that ultimately causes tyrosine phosphorylation [51, 92], which is responsible for events such as capacitation and the acrosomal reaction. Likewise, extracellular signals such as nitric oxide (NO) and carbon monoxide (CO) stimulate membrane-bound GC (mGC) and sGC, respectively, to synthesize cGMP. Increases in cGMP level evoke a concomitant increase in cAMP by inhibiting its PDE3. However, the increased Ca2+ level can also directly catalyze cAMP [93, 94]. Activated sAC, sGC, and PLC stimulate the generation of the second messengers’ inositol trisphosphate (IP3) like cAMP, cGMP. The IP3 binds to the IP3 receptor (IP3R) to increase via the release of the storage ions. Concurrently, the second messengers activate protein kinases (PKA, PKC, and PKG), in turn gating ions through the T-type calcium channels, cyclic-nucleotide gated ion channel (CNG), and so on, that together with the activation of protein tyrosine kinases (PTK) and serine/threonine protein kinase (STK) cause increased protein phosphorylation [93, 94]. Additionally, the CatSper Ca2+ activates calmodulin (Calm), phospholipase-A (PLA), and phospholipase-D (PLD) with increased generation of other second messengers during the acrosome reaction. Ca2+ influx together with increased protein phosphorylation brings about the capacitation response that is responsible for the waveform asymmetry of motility termed hyperactivation during fertilization. Both hyperactivation and the acrosomal reaction boost flagellar beating, ultimately resulting in the penetration of the outer egg coat and subsequent fertilization of the mature ovum [91–95].
