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Progesterone activates the principal Ca2+ channel of human sperm

Nature volume 471, pages 387–391 (2011)Cite this article

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Abstract

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 vestments1. Progesterone induces Ca2+ influx into spermatozoa1,2,3 and triggers multiple Ca2+-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the egg4,5,6,7,8. As an ovarian hormone, progesterone acts by regulating gene expression through a well-characterized progesterone nuclear receptor9. However, the effect of progesterone upon transcriptionally silent spermatozoa remains unexplained and is believed to be mediated by a specialized, non-genomic membrane progesterone receptor5,10. The identity of this non-genomic progesterone receptor and the mechanism by which it causes Ca2+ 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 Ca2+ 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 Ca2+ 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.

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Figure 1: Progesterone strongly potentiates human but not mouse CatSper.
Figure 2: Progesterone-activated current of human sperm is mediated by CatSper.
Figure 3: Mechanism of CatSper potentiation by progesterone.
Figure 4: Prostaglandin E 1 potentiates human CatSper.

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

    CAS  Google Scholar 

  3. Harper, C. V., Barratt, C. L. & Publicover, S. J. Stimulation of human spermatozoa with progesterone gradients to simulate approach to the oocyte. Induction of [Ca2+]i oscillations and cyclical transitions in flagellar beating. J. Biol. Chem. 279, 46315–46325 (2004)

    Article  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. Revelli, A., Massobrio, M. & Tesarik, J. Nongenomic actions of steroid hormones in reproductive tissues. Endocr. Rev. 19, 3–17 (1998)

    CAS  PubMed  Google Scholar 

  6. Roldan, E. R., Murase, T. & Shi, Q. X. Exocytosis in spermatozoa in response to progesterone and zona pellucida. Science 266, 1578–1581 (1994)

    Article  CAS  ADS  Google Scholar 

  7. Teves, M. E. et al. Progesterone at the picomolar range is a chemoattractant for mammalian spermatozoa. Fertil. Steril. 86, 745–749 (2006)

    Article  CAS  Google Scholar 

  8. Uhler, M. L., Leung, A., Chan, S. Y. & Wang, C. Direct effects of progesterone and antiprogesterone on human sperm hyperactivated motility and acrosome reaction. Fertil. Steril. 58, 1191–1198 (1992)

    Article  CAS  Google Scholar 

  9. Evans, R. M. The steroid and thyroid hormone receptor superfamily. Science 240, 889–895 (1988)

    Article  CAS  ADS  Google Scholar 

  10. Losel, R. & Wehling, M. Nongenomic actions of steroid hormones. Nature Rev. Mol. Cell Biol. 4, 46–56 (2003)

    Article  Google Scholar 

  11. 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 

  12. 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 

  13. 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 

  14. Carlson, A. E. et al. Identical phenotypes of CatSper1 and CatSper2 null sperm. J. Biol. Chem. 280, 32238–32244 (2005)

    Article  CAS  Google Scholar 

  15. Carlson, A. E. et al. CatSper1 required for evoked Ca2+ entry and control of flagellar function in sperm. Proc. Natl Acad. Sci. USA 100, 14864–14868 (2003)

    Article  CAS  ADS  Google Scholar 

  16. Qi, H. et al. All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility. Proc. Natl Acad. Sci. USA 104, 1219–1223 (2007)

    Article  CAS  ADS  Google Scholar 

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

    Article  CAS  Google Scholar 

  18. Xia, J., Reigada, D., Mitchell, C. H. & Ren, D. CATSPER channel-mediated Ca2+ entry into mouse sperm triggers a tail-to-head propagation. Biol. Reprod. 77, 551–559 (2007)

    Article  CAS  Google Scholar 

  19. Olson, S. D., Suarez, S. S. & Fauci, L. J. A model of CatSper channel mediated calcium dynamics in mammalian spermatozoa. Bull. Math. Biol. 72, 1925–1946 (2010)

    Article  MathSciNet  CAS  Google Scholar 

  20. Xia, J. & Ren, D. Egg coat proteins activate calcium entry into mouse sperm via CATSPER channels. Biol. Reprod. 80, 1092–1098 (2009)

    Article  CAS  Google Scholar 

  21. Huang, L. et al. NNC 55–0396 [(1S,2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6-fluoro-1,2,3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride]: a new selective inhibitor of T-type calcium channels. J. Pharmacol. Exp. Ther. 309, 193–199 (2004)

    Article  CAS  Google Scholar 

  22. Baulieu, E. E. Contragestion and other clinical applications of RU 486, an antiprogesterone at the receptor. Science 245, 1351–1357 (1989)

    Article  CAS  ADS  Google Scholar 

  23. Neri-Vidaurri Pdel, C., Torres-Flores, V. & Gonzalez-Martinez, M. T. A remarkable increase in the pHi sensitivity of voltage-dependent calcium channels occurs in human sperm incubated in capacitating conditions. Biochem. Biophys. Res. Commun. 343, 105–109 (2006)

    Article  Google Scholar 

  24. Aitken, R. J., Irvine, S. & Kelly, R. W. Significance of intracellular calcium and cyclic adenosine 3′,5′-monophosphate in the mechanisms by which prostaglandins influence human sperm function. J. Reprod. Fertil. 77, 451–462 (1986)

    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. Shimizu, Y. et al. Prostaglandins induce calcium influx in human spermatozoa. Mol. Hum. Reprod. 4, 555–561 (1998)

    Article  CAS  Google Scholar 

  27. Ren, D. & Xia, J. Calcium signaling through CatSper channels in mammalian fertilization. Physiology (Bethesda) 25, 165–175 (2010)

    CAS  Google Scholar 

  28. 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 

  29. 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 

  30. Liu, J., Xia, J., Cho, K. H., Clapham, D. E. & Ren, D. CatSperβ, a novel transmembrane protein in the CatSper channel complex. J. Biol. Chem. 282, 18945–18952 (2007)

    Article  CAS  Google Scholar 

  31. Strünker, T. et al. The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm. Nature doi:10.1038/nature09769 (this issue).

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Acknowledgements

This work was funded by the UCSF Program for Breakthrough Biomedical Research.

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Authors and Affiliations

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

    Polina V. Lishko, Inna L. Botchkina & Yuriy Kirichok

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  1. Polina V. Lishko
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  2. Inna L. Botchkina
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  3. Yuriy Kirichok
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Contributions

P.V.L. and Y.K. conceived the project, designed the experiments and wrote the manuscript. P.V.L. performed most of the experiments. I.L.B. helped with pilot experiments for the project. All authors discussed the results and commented on the manuscript.

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Correspondence to Yuriy Kirichok.

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The authors declare no competing financial interests.

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Lishko, P., Botchkina, I. & Kirichok, Y. Progesterone activates the principal Ca2+ channel of human sperm. Nature 471, 387–391 (2011). https://doi.org/10.1038/nature09767

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