A sperm ion channel required for sperm motility and male fertility

Abstract

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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Figure 1: Primary structure of mouse CatSper.
Figure 2: The restricted expression pattern of CatSper in testis.
Figure 3: Localization of CatSper to the plasma membrane of the principal piece of sperm.
Figure 4: Targeted disruption of CatSper.
Figure 5: Male infertility caused by CatSper disruption.
Figure 6: CatSper-/- sperm motility and in vitro fertilization defects.
Figure 7: cAMP-induced calcium influx defect in CatSper-/- sperm.
Figure 8: Summary of cyclic-nucleotide-induced Ca2+ changes.

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Acknowledgements

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.

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Correspondence to David E. Clapham.

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