title: The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm.
abstract: 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. The Ca(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(2+) channel. 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. 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.
authors.affiliation: Center of Advanced European Studies and Research, Abteilung Molekulare Neurosensorik, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany. timo.struenker@caesar.de
authors.forename: Timo
authors.initials: T
authors.lastname: Strünker
authors.forename: Normann
authors.initials: N
authors.lastname: Goodwin
authors.forename: Christoph
authors.initials: C
authors.lastname: Brenker
authors.forename: Nachiket D
authors.initials: ND
authors.lastname: Kashikar
authors.forename: Ingo
authors.initials: I
authors.lastname: Weyand
authors.forename: Reinhard
authors.initials: R
authors.lastname: Seifert
authors.forename: U Benjamin
authors.initials: UB
authors.lastname: Kaupp
mesh_terms: D000527:Alprostadil / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D000242:Cyclic AMP; D003521:Cyclopropanes / Q000494:pharmacology; D004553:Electric Conductivity; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008297:Male; D020748:Mibefradil / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D011374:Progesterone / Q000378:metabolism / Q000494:pharmacology*; D013094:Spermatozoa / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; C438823:CATSPER1 protein, human; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D003521:Cyclopropanes; D009281:Naphthalenes; C484287:NNC 55-0396; D020748:Mibefradil; D011374:Progesterone; D000242:Cyclic AMP; D000527:Alprostadil; D002118:Calcium