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The sperm‐specific CatSper channel controls the intracellular Ca 2+ concentration ([Ca 2+ ] i ) and, thereby, the swimming behaviour of sperm. In humans, CatSper is directly activated by progesterone and prostaglandins—female factors that stimulate Ca 2+ influx. Other factors including neurotransmitters, chemokines, and odorants also affect sperm function by changing [Ca 2+ ] i . Several ligands, notably odorants, have been proposed to control Ca 2+ entry and motility via G protein‐coupled receptors (GPCRs) and cAMP‐signalling pathways. Here, we show that odorants directly activate CatSper without involving GPCRs and cAMP. Moreover, membrane‐permeable analogues of cyclic nucleotides that have been frequently used to study cAMP‐mediated Ca 2+ signalling also activate CatSper directly via an extracellular site. Thus, CatSper or associated protein(s) harbour promiscuous binding sites that can host various ligands. These results contest current concepts of Ca 2+ 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 that assist sperm during their voyage across the female genital tract. The calcium channel CatSper governs sperm swimming behaviour in response to progesterone and prostaglandins. Surprisingly, multiple types of small molecules including odorants and nucleotides directly activate CatSper‐mediated calcium influx independent of G protein‐coupled receptor (GPCR) or cAMP signalling.

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. In the oviduct, cumulus cells that surround the oocyte release progesterone. In human sperm, progesterone stimulates a Ca 2+ increase by a non-genomic mechanism 1 , 2 , 3 . The Ca 2+ signal has been proposed to control chemotaxis, hyperactivation and acrosomal exocytosis of sperm 4 , 5 , 6 , 7 , 8 . However, the underlying signalling mechanism has remained mysterious. Here we show that progesterone activates the sperm-specific, pH-sensitive CatSper Ca 2+ channel 9 , 10 , 11 . We found that both progesterone and alkaline pH stimulate a rapid Ca 2+ influx with almost no latency, incompatible with a signalling pathway involving metabotropic receptors and second messengers. The Ca 2+ 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 2+ channels 10 , 11 . 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 2+ signalling in sperm and help to define further the physiological role of progesterone and CatSper.

In the oviduct, cumulus cells that surround the oocyte release progesterone. In human sperm, progesterone stimulates a Ca^sup 2+^ increase by a non-genomic mechanism. The Ca^sup 2+^ 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^sup 2+^ channel. We found that both progesterone and alkaline pH stimulate a rapid Ca^sup 2+^ influx with almost no latency, incompatible with a signalling pathway involving metabotropic receptors and second messengers. The Ca^sup 2+^ signals evoked by alkaline pH and progesterone are inhibited by the Ca^sub 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^sup 2+^ 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^sup 2+^ signalling in sperm and help to define further the physiological role of progesterone and CatSper. [PUBLICATION ABSTRACT]