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J. Biol. Chem., Vol. 280, Issue 37, 32238-32244, September 16, 2005

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Identical Phenotypes of CatSper1 and CatSper2 Null Sperm^*

Anne E. Carlson1, Timothy A. Quill¶, Ruth E. Westenbroek||, Sonya M. Schuh, Bertil Hille, and Donner F. Babcock2

From the Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195, the ^¶Department of Pharmacology, Cecil and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, and the ^||Department of Pharmacology, University of Washington, Seattle, Washington 98195

Among several candidate Ca²⁺ entry channels in sperm, only CatSper1 and CatSper2 are known to have required roles in male fertility. Past work with CatSper1 null sperm indicates that a critical lesion in hyperactivated motility underlies the infertility phenotype and is associated with an absence of depolarization-evoked Ca²⁺entry. Here we show that failure of hyperactivation of CatSper2 null sperm similarly correlates with an absence of depolarization evoked Ca²⁺ entry. Additional shared aspects of the phenotypes of CatSper1 and -2 null sperm include unperturbed regional distributions of conventional voltage-gated Ca²⁺ channel proteins and robust acceleration of the flagellar beat by bicarbonate. Further study reveals that treatment of both wild-type and CatSper2 null sperm with procaine increases beat asymmetry, a characteristic of the flagellar waveform of hyperactivation. This partial rescue of the loss-of-hyperactivation phenotype suggests that an absence of CatSper2 precludes hyperactivation by preventing delivery of needed Ca²⁺ messenger rather than by preventing flagellar responses to Ca²⁺. CatSper2 null sperm also have an increased basal cAMP content and beat frequency. Protein kinase A inhibitor H89 lowers beat frequency to that of wild-type sperm, suggesting that CatSper2 is required for protein kinase A-mediated, tonic control of resting cAMP content. Relative to wild-type testis, CatSper1 and -2 null testes contain normal amounts of CatSper2 and -1 transcripts, respectively. However, CatSper1 null sperm lack CatSper2 protein and CatSper2 null sperm lack CatSper1 protein. Hence, stable expression of CatSper1 protein requires CatSper2 and vice versa. This co-dependent expression dictates identical loss-of-function sperm phenotypes for CatSper1 and -2 null mutants.

Received for publication, February 7, 2005 , and in revised form, June 17, 2005.

^* This work was supported by U54-HD12629 of the Specialized Cooperative Centers Program in Reproduction Research of NICHD, National Institutes of Health, Grant 5R01-HD36022 and the Cecil and Ida Green Center for Reproductive Biology Sciences at the University of Texas Southwestern Medical Center. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table I.

¹ Supported in part by NIGMS Public Health Service National Research Service Award T32 GM07270.

² To whom correspondence should be addressed: Dept. of Physiology and Biophysics, MS 357290, University of Washington, Seattle, WA 98195-7290. Tel.: 206-543-6661; Fax: 206-685-0619; E-mail: donner{at}u.washington.edu.

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