Progesterone activates the principal Ca2+ channel of human sperm.

Nature 2011 Mar;471(7338):387-91

Department of Physiology, University of California San Francisco, UCSF Mail Code 2140, Genentech Hall Room N272F, 600 16th Street, San Francisco, California 94158, USA.

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. Progesterone induces Ca(2+) influx into spermatozoa and triggers multiple Ca(2+)-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the egg. As an ovarian hormone, progesterone acts by regulating gene expression through a well-characterized progesterone nuclear receptor. 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. 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 the non-genomic action of progesterone on human spermatozoa by identifying the Ca(2+) channel activated by progesterone. By applying the patch-clamp technique to mature human spermatozoa, we found that nanomolar concentrations of progesterone dramatically potentiate CatSper, a pH-dependent Ca(2+) channel of the sperm flagellum. We demonstrate that human CatSper is synergistically activated by elevation of intracellular pH and extracellular progesterone. Interestingly, human CatSper can be further potentiated by prostaglandins, but apparently through a binding site other than that of progesterone. Because our experimental conditions did not support second messenger signalling, CatSper or a directly associated protein serves as the elusive non-genomic progesterone receptor of sperm. Given that the CatSper-associated progesterone receptor is sperm specific and structurally different from the genomic progesterone receptor, it represents a promising target for the development of a new class of non-hormonal contraceptives.

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature09767DOI Listing
March 2011
6 Reads

Publication Analysis

Top Keywords

progesterone receptor
20
progesterone
16
ca2+ channel
12
human spermatozoa
12
human catsper
8
receptor sperm
8
non-genomic progesterone
8
hormone progesterone
8
human
7
receptor
6
spermatozoa
6
ca2+
5
sperm
5
spermatozoa identifying
4
channel activated
4
identifying ca2+
4
action progesterone
4
elucidate mechanism
4
mechanism non-genomic
4
non-genomic action
4

References

(Supplied by CrossRef)
Article in Nature Cell Biol.
S Publicover et al.
Nature Cell Biol. 2007
Article in J. Biol. Chem.
PF Blackmore et al.
J. Biol. Chem. 1990
Article in J. Biol. Chem.
CV Harper et al.
J. Biol. Chem. 2004
Article in Nature Rev. Mol. Cell Biol.
M Eisenbach et al.
Nature Rev. Mol. Cell Biol. 2006
Article in Endocr. Rev.
A Revelli et al.
Endocr. Rev. 1998
Article in Science
ER Roldan et al.
Science 1994
Article in Fertil. Steril.
ME Teves et al.
Fertil. Steril. 2006
Article in Fertil. Steril.
ML Uhler et al.
Fertil. Steril. 1992
Article in Science
RM Evans et al.
Science 1988
Article in Nature Rev. Mol. Cell Biol.
R Losel et al.
Nature Rev. Mol. Cell Biol. 2003
Article in Nature
D Ren et al.
Nature 2001

Similar Publications