Progesterone activates the principal Ca2+ channel of human sperm

Progesterone's role in sperm The female steroid hormone progesterone is produced by the ovaries and the placenta, and supports gestation and embryogenesis through its actions on a well-characterized nuclear progesterone receptor. But progesterone released by cells surrounding the egg also stimulates sperm cells within the Fallopian tubes and increases their fertilizing ability, and the mechanism of this action of progesterone has remained elusive. Two independent research groups now report that progesterone potently activates CatSper, the principal Ca 2+ channel of the sperm flagellum. Their data demonstrate that the CatSper channel or a directly associated membrane protein serves as a novel progesterone receptor that can mediate a fast, non-genomic effect of progesterone at the level of the sperm plasma membrane. These results should help to define the physiological role of progesterone and CatSper in sperm, and could lead to the development of new classes of non-hormonal contraceptives. Progesterone stimulates an increase in Ca 2+ levels in human sperm, but the underlying signalling mechanism is poorly understood. Two studies now show that progesterone activates the sperm-specific, pH-sensitive CatSper calcium channel, leading to a rapid influx of Ca 2+ ions into the spermatozoa. These results should help to define the physiological role of progesterone and CatSper in sperm, and could lead to the development of new classes of non-hormonal contraceptives. Steroid hormone progesterone released by cumulus cells surrounding the egg is a potent stimulator of human spermatozoa. It attracts spermatozoa towards the egg and helps them penetrate the egg’s protective vestments 1 . Progesterone induces Ca 2+ influx into spermatozoa 1 , 2 , 3 and triggers multiple Ca 2+ -dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the egg 4 , 5 , 6 , 7 , 8 . As an ovarian hormone, progesterone acts by regulating gene expression through a well-characterized progesterone nuclear receptor 9 . However, the effect of progesterone upon transcriptionally silent spermatozoa remains unexplained and is believed to be mediated by a specialized, non-genomic membrane progesterone receptor 5 , 10 . The identity of this non-genomic progesterone receptor and the mechanism by which it causes Ca 2+ entry remain fundamental unresolved questions in human reproduction. Here we elucidate the mechanism of