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

Nature volume 471, pages 382–386 (2011)Cite this article

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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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References

  1. Publicover, S., Harper, C. V. & Barratt, C. [Ca2+]i signalling in sperm – making the most of what you’ve got. Nature Cell Biol. 9, 235–242 (2007)

    Article  CAS  Google Scholar 

  2. Thomas, P. & Meizel, S. Phosphatidylinositol 4,5-bisphosphate hydrolysis in human sperm stimulated with follicular fluid or progesterone is dependent upon Ca2+ influx. Biochem. J. 264, 539–546 (1989)

    Article  CAS  Google Scholar 

  3. Blackmore, P. F., Beebe, S. J., Danforth, D. R. & Alexander, N. Progesterone and 17α-hydroxyprogesterone. Novel stimulators of calcium influx in human sperm. J. Biol. Chem. 265, 1376–1380 (1990)

    CAS  Google Scholar 

  4. Eisenbach, M. & Giojalas, L. C. Sperm guidance in mammals – an unpaved road to the egg. Nature Rev. Mol. Cell Biol. 7, 276–285 (2006)

    Article  CAS  Google Scholar 

  5. Harper, C. V., Kirkman-Brown, J. C., Barratt, C. L. R. & Publicover, S. J. Encoding of progesterone stimulus intensity by intracellular [Ca2+] ([Ca2+]I) in human spermatozoa. Biochem. J. 373, 407–417 (2003)

    Article  Google Scholar 

  6. Oren-Benaroya, R., Orvieto, R., Gakamsky, A., Pinchasov, M. & Eisenbach, M. The sperm chemoattractant secreted from human cumulus cells is progesterone. Hum. Reprod. 23, 2339–2345 (2008)

    Article  CAS  Google Scholar 

  7. Suarez, S. S. Control of hyperactivation in sperm. Hum. Reprod. Update 14, 647–657 (2008)

    Article  CAS  Google Scholar 

  8. Teves, M. E. et al. Molecular mechanism for human sperm chemotaxis mediated by progesterone. PLoS ONE 4, e8211 (2009)

    Article  ADS  Google Scholar 

  9. Ren, D. et al. A sperm ion channel required for sperm motility and male fertility. Nature 413, 603–609 (2001)

    Article  CAS  ADS  Google Scholar 

  10. Kirichok, Y., Navarro, B. & Clapham, D. E. Whole-cell patch-clamp measurements of spermatozoa reveal an alkaline-activated Ca2+ channel. Nature 439, 737–740 (2006)

    Article  CAS  ADS  Google Scholar 

  11. Lishko, P. V., Botchkina, I. L., Fedorenko, A. & Kirichok, Y. Acid extrusion from human spermatozoa is mediated by flagellar voltage-gated proton channel. Cell 140, 327–337 (2010)

    Article  CAS  Google Scholar 

  12. Gellersen, B., Fernandes, M. S. & Brosens, J. J. Non-genomic progesterone actions in female reproduction. Hum. Reprod. Update 15, 119–138 (2009)

    Article  CAS  Google Scholar 

  13. Baldi, E. et al. Nongenomic activation of spermatozoa by steroid hormones: facts and fictions. Mol. Cell. Endocrinol. 308, 39–46 (2009)

    Article  CAS  Google Scholar 

  14. Kirkman-Brown, J. C., Bray, C., Stewart, P. M., Barratt, C. L. R. & Publicover, S. J. Biphasic elevation of [Ca2+]I in individual human spermatozoa exposed to progesterone. Dev. Biol. 222, 326–335 (2000)

    Article  CAS  Google Scholar 

  15. Strünker, T. et al. A K+ -selective cGMP-gated ion channel controls chemosensation of sperm. Nature Cell Biol. 8, 1149–1154 (2006)

    Article  Google Scholar 

  16. Kaupp, U. B. et al. The signal flow and motor response controlling chemotaxis of sea urchin sperm. Nature Cell Biol. 5, 109–117 (2003)

    Article  CAS  Google Scholar 

  17. Kaupp, U. B. Olfactory signalling in vertebrates and insects: differences and commonalities. Nature Rev. Neurosci. 11, 188–200 (2010)

    Article  CAS  Google Scholar 

  18. Blackmore, P. F., Neulen, J., Lattanzio, F. & Beebe, S. J. Cell surface-binding sites for progesterone mediate calcium uptake in human sperm. J. Biol. Chem. 266, 18655–18659 (1991)

    CAS  PubMed  Google Scholar 

  19. Bedu-Addo, K. et al. Mobilisation of stored calcium in the neck region of human sperm–a mechanism for regulation of flagellar activity. Int. J. Dev. Biol. 52, 615–626 (2008)

    Article  CAS  Google Scholar 

  20. Costello, S. et al. Ca2+-stores in sperm: their identities and functions. Reproduction 138, 425–437 (2009)

    Article  CAS  Google Scholar 

  21. Parinaud, J. & Milhet, P. Progesterone induces Ca++-dependent 3′,5′-cyclic adenosine monophosphate increase in human sperm. J. Clin. Endocrinol. Metab. 81, 1357–1360 (1996)

    CAS  PubMed  Google Scholar 

  22. Spehr, M. et al. Identification of a testicular odorant receptor mediating human sperm chemotaxis. Science 299, 2054–2058 (2003)

    Article  CAS  ADS  Google Scholar 

  23. Kamenetsky, M. et al. Molecular details of cAMP generation in mammalian cells: a tale of two systems. J. Mol. Biol. 362, 623–639 (2006)

    Article  CAS  Google Scholar 

  24. Carlson, A. E., Hille, B. & Babcock, D. F. External Ca2+ acts upstream of adenylyl cyclase SACY in the bicarbonate signaled activation of sperm motility. Dev. Biol. 312, 183–192 (2007)

    Article  CAS  Google Scholar 

  25. Schaefer, M., Hofmann, T., Schultz, G. & Gudermann, T. A new prostaglandin E receptor mediates calcium influx and acrosome reaction in human spermatozoa. Proc. Natl Acad. Sci. USA 95, 3008–3013 (1998)

    Article  CAS  ADS  Google Scholar 

  26. Lishko, P. V., Botchkina, I. L. & Kirichok, Y. Progesterone activates the principal Ca2+ channel of human sperm. Nature doi:10.1038/nature09767 (this issue).

  27. Sun, F. et al. Lack of species-specificity in mammalian sperm chemotaxis. Dev. Biol. 255, 423–427 (2003)

    Article  CAS  Google Scholar 

  28. Kaupp, U. B., Kashikar, N. D. & Weyand, I. Mechanisms of sperm chemotaxis. Annu. Rev. Physiol. 70, 93–117 (2008)

    Article  CAS  Google Scholar 

  29. Sato, K. et al. Insect olfactory receptors are heteromeric ligand-gated ion channels. Nature 452, 1002–1006 (2008)

    Article  CAS  ADS  Google Scholar 

  30. Wicher, D. et al. Drosophila odorant receptors are both ligand-gated and cyclic-nucleotide-activated cation channels. Nature 452, 1007–1011 (2008)

    Article  CAS  ADS  Google Scholar 

  31. Kilic, F. et al. Caged progesterone: a new tool for studying rapid nongenomic actions of progesterone. J. Am. Chem. Soc. 131, 4027–4030 (2009)

    Article  CAS  Google Scholar 

Download references

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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Author notes

  1. Nachiket D. Kashikar

    Present address: Present address: Max Planck Institute for Biophysical Chemistry, Max Planck Research Group Sleep and Waking, Am Faßberg 11, D-37077 Göttingen, Germany.,

  2. Timo Strünker, Normann Goodwin and Christoph Brenker: These authors contributed equally to this work.

Authors and Affiliations

  1. Abteilung Molekulare Neurosensorik, Center of Advanced European Studies and Research, Ludwig-Erhard-Allee 2, 53175 Bonn, Germany,

    Timo Strünker, Normann Goodwin, Christoph Brenker, Nachiket D. Kashikar, Reinhard Seifert & U. Benjamin Kaupp

  2. Institute of Complex Systems – Cellular Biophysics (ICS-4), Forschungszentrum Jülich, 52425 Jülich, Germany ,

    Ingo Weyand

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Contributions

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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