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J. Biol. Chem., Vol. 282, Issue 33, 24397-24406, August 17, 2007

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Involvement of Cystic Fibrosis Transmembrane Conductance Regulator in Mouse Sperm Capacitation^*

Enrique O. Hernández-González¹, Claudia L. Treviño, Laura E. Castellano, José L. de la Vega-Beltrán, Ana Y. Ocampo, Eva Wertheimer^¶, Pablo E. Visconti^¶, and Alberto Darszon

From the Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca Morelos 62210, México, Departamento de Biología Celular, Centro de Investigación y Estudios Avanzados del IPN, México DF 07320, México, and the ^¶Department of Veterinary and Animal Science, University of Massachusetts, Amherst, Massachusetts 01003

Mammalian sperm acquire fertilizing ability in the female tract during a process known as capacitation. In mouse sperm, this process is associated with increases in protein tyrosine phosphorylation, membrane potential hyperpolarization, increase in intracellular pH and Ca²⁺, and hyperactivated motility. The molecular mechanisms involved in these changes are not fully known. Present evidence suggests that in mouse sperm the capacitation-associated membrane hyperpolarization is regulated by a cAMP/protein kinase A-dependent pathway involving activation of inwardly rectifying K⁺ channels and inhibition of epithelial sodium channels (ENaCs). The cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl^- channel that controls the activity of several transport proteins, including ENaCs. Here we explored whether CFTR is involved in the regulation of ENaC inhibition in sperm and therefore is essential for the capacitation-associated hyperpolarization. Using reverse transcription-PCR, Western blot, and immunocytochemistry, we document the presence of CFTR in mouse and human sperm. Interestingly, the addition of a CFTR inhibitor (diphenylamine-2-carboxylic acid; 250 µM) inhibited the capacitation-associated hyperpolarization, prevented ENaC closure, and decreased the zona pellucida-induced acrosome reaction without affecting the increase in tyrosine phosphorylation. Incubation of sperm in Cl^--free medium also eliminated the capacitation-associated hyperpolarization. On the other hand, a CFTR activator (genistein; 5-10 µM) promoted hyperpolarization in mouse sperm incubated under conditions that do not support capacitation. The addition of dibutyryl cyclic AMP to noncapacitated mouse sperm elevated intracellular Cl^-. These results suggest that cAMP-dependent Cl^- fluxes through CFTR are involved in the regulation of ENaC during capacitation and thus contribute to the observed hyperpolarization associated with this process.

Received for publication, February 23, 2007 , and in revised form, June 15, 2007.

^* This work was supported by National Institutes of Health Grants HD38082 and HD44044 (to P. E. V.); by Fogarty International Collaboration Award Grant RO3 TW 006121 (to P. E. V. and A. D.); and by funds from Consejo Nacional de Ciencia y Tecnologia-México 49113 (to A. D.), Direccion General de Asuntos del Personal Academico/Universidad Nacional Autónoma de México IN225406 (to A. D.) and IN227806-3 (to C. T.), and the Wellcome Trust (to A. D.). 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.

¹ To whom correspondence should be addressed: Dept. de Biología Celular, Centro de Investigación y Estudios Avanzados del IPN, Avenida Instituto Politécnico Nacional 2508, San Pedro Zacatenco, México DF 07360, México. Tel.: 52-50613352; Fax: 52-50613393; E-mail: eoton{at}cell.cinvestav.mx.

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