AUTHOR=Balbach Melanie , Hamzeh Hussein , Jikeli Jan F. , Brenker Christoph , Schiffer Christian , Hansen Jan N. , Neugebauer Pia , Trötschel Christian , Jovine Luca , Han Ling , Florman Harvey M. , Kaupp U. Benjamin , Strünker Timo , Wachten Dagmar TITLE=Molecular Mechanism Underlying the Action of Zona-pellucida Glycoproteins on Mouse Sperm JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=8 YEAR=2020 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.572735 DOI=10.3389/fcell.2020.572735 ISSN=2296-634X 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 sufficiently negative 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.