Sperm mystery solved

Scientists have solved a 20-year mystery regarding the molecular mechanism by which human sperm detect an egg. The answer lies in a unique ion channel that senses progesterone, causing an influx of calcium into the sperm cells. The finding, published in a pair of papers this week in linkurl:Nature,;http://www.nature.com/nature provides a clue to some types of male infertility, and could someday be the foundation for a non-hormonal contraceptive.

Illustration by linkurl:Carin Cain;http://www.carincain.com/home/

"It's a real step forward," said linkurl:Steve Publicover,;http://biosciences-people.bham.ac.uk/About/staff_profiles_contact.asp?ID=45 who studies human sperm at the University of Birmingham in the UK and was not involved in the research. "It gives us a handle on what is going on in sperm." Prior to fertilization, a cloud of cumulus cells surrounding the egg release progesterone, the female sex hormone, triggering a calcium influx into the sperm. This flood of calcium causes the sperm to beat their flagella rapidly, an action necessary to penetrate though the egg's protective jelly-like protein coating. Progesterone has also been implicated in providing a chemical gradient by which sperm can navigate toward the egg. But how progesterone activates sperm has remained unknown. In most human cells, progesterone binds nuclear receptors inside the cell and activates transcription. Sperm, however, are transcriptionally silent, so scientists have searched for a different mechanism by which progesterone activates them, such as a receptor on the external membrane of the cell. "It was a scientific mystery -- a puzzle," said linkurl:U.B. Kaupp;http://www2.fz-juelich.de/isb/isb-1//kaupp_ub of the Center of Advanced European Studies and Research, senior author of the first paper. Unfortunately, that mystery has remained unsolved for 20 years. Sperm are notoriously difficult to study: they are extremely small -- the smallest cells in the human body, in fact -- and motile, with a compressed nucleus and almost no cytoplasm. In addition, progesterone does not activate mouse sperm in the same way as it does human sperm, a crucial difference between species. "People have tried a lot [to find the receptor], but it's been immensely difficult," said Publicover, who wrote an accompanying News & Views article in Nature.Now, however, in two papers published simultaneously this week, researchers at the University of California, San Francisco, and the Center of Advanced European Study and Research in Bonn, Germany, have identified the calcium channel that senses progesterone and causes an influx of calcium into the cell -- CatSper, a membrane protein first discovered in 2001 that resides only in the tails of sperm, not in any other cell type in the human body. Using whole-cell patch clamping to record currents across the membrane of a cell -- a technique first used on human sperm at linkurl:UCSF in 2009;http://www.the-scientist.com/blog/display/57133/ -- the teams demonstrated that the current induced by progesterone and the current caused by the activation of CatSper are indistinguishable. In addition, blocking CatSper inhibits the ability of progesterone to activate the sperm cell. "The data are really, really convincing," said Publicover. "It's very persuasive."Because of the instantaneous rise of calcium in sperm following exposure to progesterone, Kaupp's team concluded that the receptor is not a G-protein coupled receptor or part of a second messenger signaling system. "We think that progesterone acts directly as a ligand that binds this channel and gates it open," said Kaupp. Still, more research is needed to identify the site of progesterone binding on CatSper and determine what type of ion channel it is.Mutations in the CatSper have been linked to human male infertility. The discovery suggests that a human sperm cell with defective CatSper channels cannot respond to the progesterone released by the cumulus cells and therefore won't be able to fertilize the egg. In addition, the receptor may be a promising target for contraceptive therapies. Because an antagonist specific to CatSper wouldn't affect any other cells in the body, unlike current hormone steroid treatments, it would have fewer side effects. "CatSper is viewed as one of the best targets in a new class of contraceptives," said linkurl:Polina Lishko;http://ucsf.academia.edu/PolinaLishko of UCSF, lead author of the second paper. "Once we identify the binding site, there is a potential to design a drug which won't resemble steroids at all." Strunker, T., et al., "The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm," Nature, 471:382-6. Lishko, P.V., et al., "Progesterone activates the principal Ca2+ channel of human sperm," Nature, 471:387-91, 2011.
**__Related stories:__*** linkurl:Slow sperm prevent inbreeding;http://www.the-scientist.com/news/display/57919/
[12th January 2011]*linkurl:Sperm motility secrets revealed;http://www.the-scientist.com/news/display/57133/
[4th February 2010]
**__Related F1000 Evaluations:__***linkurl:A sperm ion channel required for sperm motility and male fertility;http://f1000.com/1002013?key=lf95w3rl16j24d9
D. Ren et al., Nature, 413:603-9, 2001. Evaluated Anthony Means, Duke Univ Medical Center; Roger Hardie, Univ of Cambridge; Gary Yellen, Harvard Medical School *linkurl:Association of Catsper1 or -2 with Ca(v)3.3 leads to suppression of T-type calcium channel activity;http://f1000.com/1032672?key=73nbzllkh1q4tsm
D. Zhang et al., J Biol Chem, 281:22332-41, 2006. Evaluated by Harvey Florman, Univ of Massachusetts Medical School.

Sperm mystery solved

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