Molecular Mechanism Underlying the Action of Zona-pellucida Glycoproteins on Mouse Sperm
Melanie Balbach, Hussein Hamzeh, Jan F. Jikeli, Christoph Brenker, Christian Schiffer, Jan N. Hansen, Pia Neugebauer, Christian Trötschel, Luca Jovine, Ling Han, Harvey M. Florman, U. Benjamin Kaupp, Timo Strünker, Dagmar Wachten
Abstract
Mammalian oocytes are enveloped by the zona pellucida (ZP), an extracellular matrix of glycoproteins. In sperm, stimulation with ZP proteins evokes a rapid Ca2+ influx via the sperm-specific, pH-sensitive Ca2+ channel CatSper. However, the physiological role and molecular mechanisms underlying ZP-dependent activation of CatSper are unknown. Here, we delineate the sequence of ZP-signaling events in mouse sperm. We show that ZP proteins evoke a rapid intracellular pHi increase that rests predominantly on Na+/H+ exchange by NHA1 and requires cAMP synthesis by the soluble adenylyl cyclase sAC as well as a hyperpolarized membrane potential set by the spem-specific K+ channel Slo3. The alkaline-activated CatSper channel translates the ZP-induced pHi increase into a Ca2+ response. Our findings reveal the molecular components underlying ZP action on mouse sperm, opening up new avenues for understanding the basic principles of sperm function and, thereby, mammalian fertilization.