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

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 Zn2+ in millimolar concentrations, whereas in the female reproductive tract, the concentration is around 1 mu M. In this study, we characterize the role of Zn2+ in human sperm capacitation focusing on its effect on HAM. Western blot analysis revealed the presence of GPR39-type Zn-receptor localized mainly in the sperm tail. Zn2+ at micromolar concentration stimulates HAM, which is mediated by a cascade involving GPR39-adenylyl cyclase (AC)-cyclic AMP (cAMP)-protein kinase A-tyrosine kinase Src (Src)-epidermal growth factor receptor and phospholipase C. Both the transmembrane AC and the soluble-AC are involved in the stimulation of HAM by Zn2+. The development of HAM is precisely regulated by cAMP, in which relatively low concentration (5-10 mu M) stimulated HAM, whereas at 30 mu M no stimulation occurred. A similar response was seen when different concentrations of Zn2+ were added to the cells; low Zn2+ stimulated HAM, whereas at relatively high Zn2+, no effect was seen. We further demonstrate that the Ca2+-channel CatSper involved in Zn2+-stimulated HAM. These data support a role for extracellular Zn2+ acting via GPR39 to regulate signaling pathways in sperm capacitation, leading to HAM induction.