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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 Ca2+ increase by a non-genomic mechanism1,2,3. The Ca2+ signal has been proposed to control chemotaxis, hyperactivation and acrosomal exocytosis of sperm4,5,6,7,8. However, the underlying signalling mechanism has remained mysterious. Here we show that progesterone activates the sperm-specific, pH-sensitive CatSper Ca2+ channel9,10,11. We found that both progesterone and alkaline pH stimulate a rapid Ca2+ influx with almost no latency, incompatible with a signalling pathway involving metabotropic receptors and second messengers. The Ca2+ signals evoked by alkaline pH and progesterone are inhibited by the Cav 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 Ca2+ channels10,11. 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 Ca2+ signalling in sperm and help to define further the physiological role of progesterone and CatSper.

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Figure 1: Progesterone-induced Ca 2+ signals in human sperm.
Figure 2: Progesterone does not activate a cAMP-signalling pathway.
Figure 3: Pharmacology of progesterone-induced Ca 2+ signals.
Figure 4: Electrophysiological characterization of whole-cell CatSper currents from human sperm cells.

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Acknowledgements

This work was supported by the German Research Foundation (SFB 645) and the International Helmholtz Research School on Biophysics and Soft Matter. We thank S. Stark for technical assistance, H. Krause and B. Kayser for preparing the manuscript, and C. Bernsdorff for preparing the figures. The caged compounds were kindly provided by V. Hagen.

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T.S., N.G., C.B., N.K. and I.W. designed and performed experiments. R.S. designed experiments. T.S. and U.B.K. conceived the project. T.S. and U.B.K. wrote the manuscript. All authors revised and edited the manuscript.

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Correspondence to Timo Strünker or U. Benjamin Kaupp.

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The authors declare no competing financial interests.

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Strünker, T., Goodwin, N., Brenker, C. et al. The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm. Nature 471, 382–386 (2011). https://doi.org/10.1038/nature09769

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