Signaling pathways involved in human sperm hyperactivated motility stimulated by Zn²⁺

Abstract

To fertilize the egg, sperm cells must reside in the female reproductive tract for several hours during which they undergo chemical and motility changes collectively called capacitation. During capacitation, the sperm develop a unique type of motility known as hyperactivated motility (HAM). The semen contains Zn 2+ in millimolar concentrations, whereas in the female reproductive tract the concentration is around 1 µM. In this study, we characterize the role of Zn 2+ in human sperm capacitation focusing on its effect on HAM. Western blot analysis revealed the presence of G protein-coupled receptor 39 (GPR39) type Zn-receptor localized mainly in the sperm tail. Zn 2+ at micromolar concentration stimulates HAM, which is mediated by a cascade involving GPR39-AC-cAMP-PKA-Src-EGFR and phospholipase C. Both the transmembrane adenylyl cyclase (AC) and the soluble-AC are involved in the stimulation of HAM by Zn 2+ . The development of HAM is precisely regulated by cyclic adenosine monophosphate, in which relatively low concentration (5-10 µM) stimulated HAM, whereas at 30 µM no stimulation occurred. A similar responsewas seen when different concentrations of Zn 2+ were added to the cells; low Zn 2+ stimulated HAM, whereas at relatively high Zn 2+ , no effect was seen. We further demonstrate that the Ca 2+ -channel CatSper involved in Zn 2+ -stimulated HAM. These data support a role for extracellular Zn 2+ acting via GPR39 to regulate signaling pathways in sperm capacitation, leading to HAM induction.

Effects of zinc chloride on boar sperm quality during liquid storage at 17°C

“…One of the most active antioxidant enzyme in semen is copper‐zinc superoxide dismutase (CuZnSOD). Zn participates in oxidation and reduction, while Zn and Cu act as cofactors of CuZn‐SOD to prevent the harmful effects of reactive oxygen species (ROS) to sperm (Deborah et al., 2019 ). In the present study, the addition of ZnCl 2 increased T‐AOC and CuZn‐SOD activity and reduced the MDA content of sperm ( p < 0.05), demonstrating that supplementation with antioxidants can protect sperm from oxidative stress.…”

The Action of Reproductive Fluids and Contained Steroids, Prostaglandins, and Zn2+ on CatSper Ca2+ Channels in Human Sperm

“…In fact, the action of Zn 2+ in sperm and its role during fertilization are complex and only ill-defined ( Allouche-Fitoussi and Breitbart, 2020 ). It has been reported that seminal Zn 2+ decreases sperm motility and that the motility is stimulated only upon its removal ( Allouche-Fitoussi and Breitbart, 2020 ); in sperm purified from the ejaculate, stimulation with low micromolar Zn 2+ concentrations evoked hyperactivated motility ( Allouche-Fitoussi et al, 2018 ; Allouche-Fitoussi and Breitbart, 2020 ). Our results suggest an even more complex control of motility by a Zn 2+ /prostaglandin interplay, which needs to be scrutinized in future studies that investigate the motility responses of sperm upon dilution from the ejaculate and/or upon stimulation with dilutions of Zn 2+ /prostaglandin mixtures.…”

Signaling Enzymes Required for Sperm Maturation and Fertilization in Mammals

“…Prevention of the increase in pHi or loss of CatSper leads to infertility. A recent study shows that CatSper channels also mediate Zn 2+ -dependent stimulation of sperm hyperactivation (Allouche-Fitoussi et al, 2018). A model for sperm hyperactivation incorporating the functions of cAMP-PKA, calcium, and pHi is shown in Figure 1.…”