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Abstract

In the oviduct, cumulus cells that surround the oocyte release progesterone. In human sperm, progesterone stimulates a Ca2+ increase by a non-genomic mechanism. The Ca2+ signal has been proposed to control chemotaxis, hyperactivation, and acrosomal exocytosis of sperm. However, the underlying signalling mechanism has remained mysterious. Here we show that progesterone activates the sperm-specific, pH-sensitive CatSper Ca2+ channel. Both progesterone and alkaline pH stimulate a rapid Ca2+ influx with almost no latency, incompatible with a signalling pathway involving metabotropic receptors and second messengers. The Ca2+ signals evoked by alkaline pH and progesterone are inhibited by the Cav channel blockers NNC 55-0396 and mibefradil. Patch-clamp recordings from sperm reveal an alkaline-activated current carried by mono- and divalent ions that exhibits all the hallmarks of sperm-specific CatSper Ca2+ channels. Progesterone substantially enhances the CatSper current. The alkaline- and progesterone-activated CatSper current is inhibited by both drugs. Our results resolve a long-standing controversy on the non-genomic progesterone signalling. In human sperm, either the CatSper channel itself or an associated protein serve as the non-genomic progesterone receptor. The identification of CatSper channel blockers will greatly facilitate the study of Ca2+ signalling in sperm and help to define further the physiological role of progesterone and CatSper. However, a plethora of other substances, including odorants evoke similar Ca2+ responses, suggesting that a signalling cascade similar to olfactory neurons of the nose also exists in sperm and mediates chemotaxis in the oviduct. It came as a surprise to discover that CatSper channels are opened by many other substances, in particular odorants at high concentrations. These results contest current concepts of Ca2+ signalling by GPCR and cAMP in mammalian sperm. Ligands thought to activate metabotropic pathways, in fact, act via a common ionotropic mechanism. We propose that the CatSper channel complex serves as a polymodal sensor for multiple chemical cues in the female genital tract.