Protein C Inhibitor May Modulate Human Sperm-Oocyte Interactions1

Abstract

Protein C inhibitor (PCI) is a heparin-binding plasma serine protease inhibitor that was originally identified as an inhibitor of activated protein C. PCI has a broad protease specificity, inhibiting several proteases in hemostasis and fibrinolysis by acting as a suicide substrate. Recently it has been reported that proteases of the reproductive system, such as acrosin, prostate-specific antigen, and tissue kallikrein, can also be effectively inhibited by PCI. However, a direct relation between PCI and physiological events during fertilization has not yet been established. An attempt was made to monitor and localize the inhibition of the sperm protease acrosin by PCI. Localization experiments for PCI on epididymal spermatozoa showed that PCI is present on the acrosomal cap of human spermatozoa, which demonstrates the early presence of PCI in the male reproductive tract. Induction of the acrosome reaction in ejaculated human spermatozoa resulted in the disappearance of PCI from the plasma membrane overlying the acrosomal head and the appearance of a strict distribution at the equatorial segment of human spermatozoa. The activity of acrosin in sperm extracts could be effectively inhibited by PCI. Zona-binding assays showed that active PCI is able to block sperm-egg binding in a concentration-dependent manner. The combination of the potent inhibition of acrosin and sperm-egg binding by PCI and the localization studies suggested that PCI may protect spermatozoa against premature acrosome reaction and degradation, thereby modulating the acrosin activity so that it can coincide with binding to the oocyte.

Characterization and expression analysis of serpins in the Chinese mitten crab Eriocheir sinensis

“…8C-H), and could not be detected at 40 min (Fig.8I, J). Our results are similar to those observed with HongrES1 and Protein C Inhibitor; the expression of these two serpins were shown to be reduced during the AR (Elisen et al, 1998;Ni et al, 2009). Therefore, Esserpin-3 may control the AR process in E. sinensis in a manner similar to HongrES1 and Protein C Inhibitor as a decapacitation factor.…”

“…For example, Protein C Inhibitor, a serpin protein secreted into the seminal fluid, can protect sperm, and is depleted during the acrosome reaction (AR) (Elisen et al, 1998). In murine, serpin2 binds to epididymal sperm and may block fertilization by inhibiting sperm capacitation and preventing sperm binding to the egg (Lu et al, 2011).…”

Disruption of the protein C inhibitor gene results in impaired spermatogenesis and male infertility

“…On the other hand, it has also been suggested that PCI bound to seminal coagula might control their liquefaction by inhibiting proteolytic degradation of semenogelin I and II by PSA (33). Others (7,34) and we (35) have shown that PCI interferes with sperm-egg binding and with in vitro fertilization, possibly due to its ability to inhibit the sperm protease acrosin (7,8). However, here too the in vivo relevance of these in vitro findings is questionable, since homozygous male mice with targeted disruption of the acrosin gene are fertile (36).…”

Caspase-Independent Exposure of Aminophospholipids and Tyrosine Phosphorylation in Bicarbonate Responsive Human Sperm Cells1

“…Samples were allowed to liquefy at room temperature for 2 h. Semen was diluted to 15 ϫ 10 6 cells/ml in saline medium containing 137 mM NaCl, 2.5 mM KCl, 10 mM glucose, and 20 mM Hepes (pH 7.4) and washed through isotonic Percoll as described previously [10]. Washed spermatozoa were diluted up to 10 7 cells/ml in Hepes-buffered Tyrode medium (HBT-control: 120 mM NaCl, 21 The HTF-control was also isotonically supplemented with 24 mM bicarbonate (HTF-Bic) [22].…”