Calcium and cyclic nucleotides have crucial roles in mammalian fertilization, but the molecules comprising the Ca2+-permeation pathway in sperm motility are poorly understood. Here we describe a putative sperm cation channel, CatSper, whose amino-acid sequence most closely resembles a single, six-transmembrane-spanning repeat of the voltage-dependent Ca2+-channel four-repeat structure. CatSper is located specifically in the principal piece of the sperm tail. Targeted disruption of the gene results in male sterility in otherwise normal mice. Sperm motility is decreased markedly in CatSper-/- mice, and CatSper-/- sperm are unable to fertilize intact eggs. In addition, the cyclic-AMP-induced Ca2+ influx is abolished in the sperm of mutant mice. CatSper is thus vital to cAMP-mediated Ca2+ influx in sperm, sperm motility and fertilization. CatSper represents an excellent target for non-hormonal contraceptives for both men and women.
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Wassarman, P. M., Jovine, L. & Litscheer, E. S. A profile of fertilization in mammals. Nature Cell Biol. 3, E59–E64 (2001).
Yanagimachi, R. in The Physiology of Reproduction (eds Knobill, E. & Neill, J. D. ) 189–315 (Raven, New York, 1994).
O'Toole, C. M., Arnoult, C., Darszon, A., Steinhardt, R. A. & Florman, H. M. Ca2+ entry through store-operated channels in mouse sperm is initiated by egg ZP3 and drives the acrosome reaction. Mol. Biol. Cell 11, 1571–1584 (2000).
Jungnickel, M. K., Marrero, H., Birnbaumer, L., Lemos, J. R. & Florman, H. M. Trp2 regulates entry of Ca2+ into mouse sperm triggered by egg ZP3. Nature Cell Biol. 3, 499–502 (2001).
Bedford, J. M. Mammalian fertilization misread? Sperm penetration of the eutherian zona pellucida is unlikely to be a lytic event. Biol. Reprod. 59, 1275–1287 (1998).
Tash, J. S. in Controls of Sperm Motility: Biological and Clinical Aspects (ed. Gagnon, C.) 229–240 (CRC, Boca Raton, 1990).
Darszon, A., Labarca, P., Nishigaki, T. & Espinosa, F. Ion channels in sperm physiology. Physiol. Rev. 79, 481–510 (1999).
Hyne, R. V. & Garbers, D. L. Calcium-dependent increase in adenosine 3′,5′-monophosphate and induction of the acrosome reaction in guinea pig spermatozoa. Proc. Natl Acad. Sci. USA 76, 5699–5703 (1979).
Serrano, C. J., Trevino, C. L., Felix, R. & Darszon, A. Voltage-dependent Ca2+ channel subunit expression and immunolocalization in mouse spermatogenic cells and sperm. FEBS Lett. 462, 171–176 (1999).
Weyand, I. et al. Cloning and functional expression of a cyclic-nucleotide-gated channel from mammalian sperm. Nature 368, 859–863 (1994).
Wiesner, B. et al. Cyclic nucleotide-gated channels on the flagellum control Ca2+ entry into sperm. J. Cell Biol. 142, 473–484 (1998).
Santi, C. M., Darszon, A. & Hernandez-Cruz, A. A dihydropyridine-sensitive T-type Ca2+ current is the main Ca2+ current carrier in mouse primary spermatocytes. Am. J. Physiol. 271, C1583–C1593 (1996).
Arnoult, C., Cardullo, R. A., Lemos, J. R. & Florman, H. M. Activation of mouse sperm T-type Ca2+ channels by adhesion to the egg zona pellucida. Proc. Natl Acad. Sci. USA 93, 13004–13009 (1996).
Wennemuth, G., Westenbroek, R. E., Xu, T., Hille, B. & Babcock, D. F. CaV2.2 and CaV2.3 (N- and R-type) Ca2+ channels in depolarization-evoked entry of Ca2+ into mouse sperm. J. Biol. Chem. 275, 21210–21217 (2000).
Ertel, E. A. et al. Nomenclature of voltage-gated calcium channels. Neuron 25, 533–535 (2000).
Ellinor, P. T., Yang, J., Sather, W. A., Zhang, J. F. & Tsien, R. W. Ca2+ channel selectivity at a single locus for high-affinity Ca2+ interactions. Neuron 15, 1121–1132 (1995).
Aoki, F., Sakai, S. & Kohmoto, K. Regulation of flagellar bending by cAMP and Ca2+ in hamster sperm. Mol. Reprod. Dev. 53, 77–83 (1999).
Espinosa, F. et al. Mouse sperm patch-clamp recordings reveal single Cl- channels sensitive to niflumic acid, a blocker of the sperm acrosome reaction. FEBS Lett. 426, 47–51 (1998).
Kobori, H., Miyazaki, S. & Kuwabara, Y. Characterization of intracellular Ca2+ increase in response to progesterone and cyclic nucleotides in mouse spermatozoa. Biol. Reprod. 63, 113–120 (2000).
Perez, G. I. et al. Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency. Nature Genet. 21, 200–203 (1999).
Arnoult, C., Lemos, J. R. & Florman, H. M. Voltage-dependent modulation of T-type calcium channels by protein tyrosine phosphorylation. EMBO J. 16, 1593–1599 (1997).
We thank K. Wickman and W. Pu for advice on embryonic stem cell handling; G. Krapivinsky and X. Wei for assistance with antibody work and confocal microscopy, respectively; M. Ericsson for electron microscopy; H. Florman, D. Babcock, C. Santi and A. Darszon for advice on spermatocyte and sperm preparation; M. Biel and K.-W. Yau for CNG clones; and D. Garbers and T. Quill for helpful discussions and advice. B.N. was supported by Centro Internacional de Fisica, Lab. de Biofisica, Bogota, Columbia. This work was supported by the Howard Hughes Medical Institute.
About this article
Research update and opportunity of non-hormonal male contraception: Histone demethylase KDM5B-based targeting
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