All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility

  1. Huayu Qi*,
  2. Magdalene M. Moran*,†,
  3. Betsy Navarro*,
  4. Jayhong A. Chong*,†,
  5. Grigory Krapivinsky*,
  6. Luba Krapivinsky*,
  7. Yuriy Kirichok*,
  8. I. Scott Ramsey*,
  9. Timothy A. Quill‡, and
  10. David E. Clapham*,§
  1. *Department of Cardiology, Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Enders 1309, Children's Hospital Boston, 320 Longwood Avenue, Boston, MA 02115; and
  2. ‡Cecil H. and Ida Green Center for Reproductive Biology Sciences, Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390

  1. Contributed by David E. Clapham, November 29, 2006

Abstract

Mammalian spermatozoa become motile at ejaculation, but before they can fertilize the egg, they must acquire more thrust to penetrate the cumulus and zona pellucida. The forceful asymmetric motion of hyperactivated spermatozoa requires Ca2+ entry into the sperm tail by an alkalinization-activated voltage-sensitive Ca2+-selective current (I CatSper). Hyperactivation requires CatSper1 and CatSper2 putative ion channel genes, but the function of two other related genes (CatSper3 and CatSper4) is not known. Here we show that targeted disruption of murine CatSper3 or CatSper4 also abrogated I CatSper, sperm cell hyperactivated motility and male fertility but did not affect spermatogenesis or initial motility. Direct protein interactions among CatSpers, the sperm specificity of these proteins, and loss of I CatSper in each of the four CatSper −/− mice indicate that CatSpers are highly specialized flagellar proteins.

Footnotes

  • §To whom correspondence should be addressed. E-mail: dclapham{at}enders.tch.harvard.edu

  • ↵ †Present address: Hydra Biosciences, 790 Memorial Drive, Cambridge, MA 02139.

  • Author contributions: H.Q., M.M.M., and B.N. contributed equally to this work; D.E.C. designed research; H.Q., M.M.M., B.N., J.A.C., G.K., L.K., Y.K., I.S.R., and T.A.Q. performed research; M.M.M., G.K., and L.K. contributed new reagents/analytic tools; H.Q., M.M.M., B.N., J.A.C., G.K., Y.K., T.A.Q., and D.E.C. analyzed data; and H.Q. and D.E.C. wrote the paper.

  • Conflict of interest: M.M.M. and J.A.C. are employees of Hydra Biosciences, a company with pending patents related to CatSper protein function. As employees, both have stock options in Hydra Biosciences. D.E.C. also owns stock in Hydra Biosciences. All other authors have no conflict of interest.

  • Data deposition: The sequences reported in this paper have been deposited in the GenBank database [accession nos. AAP21831 (mCatSper3, originally called mCatSper4) and NP_808534 (mCapSper4)].

  • See Commentary on page 1107.

  • This article contains supporting information online at www.pnas.org/cgi/content/full/ 0610286104/DC1.

  • Abbreviation:
    DVF,
    divalent free.

  • Freely available online through the PNAS open access option.

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  1. Published online before print January 16, 2007, doi: 10.1073/pnas.0610286104 PNAS January 23, 2007 vol. 104 no. 4 1219-1223
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