Signaling pathways involved in human sperm hyperactivated motility stimulated by Zn ²⁺

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 response was 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.