The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm

Nature. 2011 Mar 17;471(7338):382-6. doi: 10.1038/nature09769.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alprostadil / pharmacology
  • Benzimidazoles / pharmacology
  • Calcium / metabolism*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels / metabolism*
  • Calcium Signaling / drug effects*
  • Cyclic AMP
  • Cyclopropanes / pharmacology
  • Electric Conductivity
  • Humans
  • Hydrogen-Ion Concentration
  • Male
  • Mibefradil / pharmacology
  • Naphthalenes / pharmacology
  • Patch-Clamp Techniques
  • Progesterone / metabolism
  • Progesterone / pharmacology*
  • Spermatozoa / drug effects*
  • Spermatozoa / metabolism*


  • Benzimidazoles
  • CATSPER1 protein, human
  • Calcium Channel Blockers
  • Calcium Channels
  • Cyclopropanes
  • Naphthalenes
  • NNC 55-0396
  • Mibefradil
  • Progesterone
  • Cyclic AMP
  • Alprostadil
  • Calcium