The CatSper channel mediates progesterone-induced Ca influx in human sperm

In the oviduct, cumulus cells that surround the oocyte release progesterone. In human sperm, progesterone stimulates a Ca increase by a non-genomic mechanism. The Ca 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 Ca channel. We found that both progesterone and alkaline pH stimulate a rapid Ca influx with almost no latency, incompatible with a signalling pathway involving metabotropic receptors and second messengers. The Ca signals evoked by alkaline pH and progesterone are inhibited by the Ca v 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 Ca 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 over the non-genomic progesterone signalling. In human sperm, either the CatSper channel itself or an associated protein serves as the non-genomic progesterone receptor. The identification of CatSper channel blockers will greatly facilitate the study of Ca signalling in sperm and help to define further the physiological role of progesterone and CatSper. © 2011 Macmillan Publishers Limited. All rights reserved.