Editors' ChoiceReproduction

Activating CatSper

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Science Signaling  22 Mar 2011:
Vol. 4, Issue 165, pp. ec84
DOI: 10.1126/scisignal.4165ec84

Progesterone, like other steroid hormones, has classically been viewed as acting through a nuclear receptor to mediate changes in gene transcription. Thus, the mechanism whereby progesterone released from cumulus cells surrounding the egg elicits calcium influx in human sperm—which are transcriptionally inactive—has been enigmatic (see Publicover and Barratt). Now, two groups, Strünker et al. and Lishko et al., combined whole-cell patch clamp analysis of human spermatozoa with complementary techniques (calcium imaging for Strünker et al. and patch clamp recording from isolated sperm flagella for Lishko et al.) to show that progesterone activates the pH-dependent, sperm-specific calcium channel CatSper. The rapidity of the calcium response argued for a direct extracellular effect of progesterone on a membrane protein; moreover, Lishko et al. showed that a membrane-impermeant conjugate of progesterone and bovine serum albumin could activate human CatSper currents, and Strünker et al. eliminated a role for cAMP signaling. Both groups found that progesterone enhanced an inward current in human sperm with pharmacological sensitivity and biophysical properties identical to the CatSper current activated by alkaline pH. Like alkaline pH, with which it acted synergistically, progesterone shifted the voltage dependence of human CatSper activation to more negative voltages. Certain prostaglandins also activated human CatSper, likely through a binding site distinct from that of progesterone. Thus, both groups conclude that CatSper itself—or an associated membrane protein that functions in a complex with it—most likely acts as the receptor whereby progesterone stimulates calcium influx in human spermatozoa.

T. Strünker, N. Goodwin, C. Brenker, N. D. Kashikar, I. Weyand, R. Seifert, U. B. Kaupp, The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm. Nature 471, 382–386 (2011). [PubMed]

P. V. Lishko, I. L. Botchkina, Y. Kirichok, Progesterone activates the principal Ca2+ channel of human sperm. Nature 471, 387–391 (2011). [PubMed]

S. Publicover, C. Barratt, Progesterone’s gateway into sperm. Nature 471, 313–314 (2011). [PubMed]

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