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Molecular Mechanism Underlying the Action of Zona-pellucida Glycoproteins on Mouse Sperm.

Frontiers in cell and developmental biology (2020-09-29)
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 pH i increase that rests predominantly on Na+/H+ exchange by NHA1 and requires cAMP synthesis by the soluble adenylyl cyclase sAC as well as a sufficiently negative membrane potential set by the spem-specific K+ channel Slo3. The alkaline-activated CatSper channel translates the ZP-induced pH i 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.

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