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J. Biol. Chem. 279 (38): 40194-40203

© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.

Particulate Adenylate Cyclase Plays a Key Role in Human Sperm Olfactory Receptor-mediated Chemotaxis*

Marc Spehr{ddagger}§, Katlen Schwane¶, Jeffrey A. Riffell||, Jon Barbour¶, Richard K. Zimmer||**, Eva M. Neuhaus¶, , and Hanns Hatt¶

{ddagger}Department of Anatomy and Neurobiology, University of Maryland, Baltimore, Maryland 21201, the Lst. Zellphysiologie, Ruhr-Universität Bochum, Universitätsstrasse 150, 44780 Bochum, Germany, the ||Department of Ecology and Evolutionary Biology, University of California, Los Angeles, California 90095-1606, and the **Department of Neurosciences, Brain Research Institute, University of California, Los Angeles, California 90095-1606

Abstract: Human sperm chemotaxis is a critical component of the fertilization process, but the molecular basis for this behavior remains unclear. Recent evidence shows that chemotactic responses depend on activation of the sperm olfactory receptor, hOR17-4. Certain floral scents, including bourgeonal, activate hOR17-4, trigger pronounced Ca2+ fluxes, and evoke chemotaxis. Here, we provide evidence that hOR17-4 activation is coupled to a cAMP-mediated signaling cascade. Multidimensional protein identification technology was used to identify potential components of a G-protein-coupled cAMP transduction pathway in human sperm. These products included various membrane-associated adenylate cyclase (mAC) isoforms and the Golf-subunit. Using immunocytochemistry, specific mAC isoforms were localized to particular cell regions. Whereas mAC III occurred in the sperm head and midpiece, mAC VIII was distributed predominantly in the flagellum. In contrast, Golf was found mostly in the flagellum and midpiece. The observed spatial distribution patterns largely correspond to the spatiotemporal character of hOR17-4-induced Ca2+ changes. Behavioral and Ca2+ signaling responses of human sperm to bourgeonal were bioassayed in the presence, or absence, of the adenylate cyclase antagonist SQ22536. This specific agent inhibits particulate AC, but not soluble AC, activation. Upon incubation with SQ22536, cells ceased to exhibit Ca2+ signaling, chemotaxis, and hyperactivation (faster swim speed and flagellar beat rate) in response to bourgeonal. Particulate AC is therefore required for induction of hOR17-4-mediated human sperm behavior and represents a promising target for future design of contraceptive drugs.

Received for publication April 8, 2004. Revision received July 6, 2004.

* This work was supported by the Alma und Heinrich Vogelsang Stiftung. 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.

§ To whom correspondence should be addressed: Dept. Anatomy and Neurobiology, School of Medicine, University of Maryland, 685 West Baltimore St., Baltimore, MD 21201. Tel.: 410-706-8921; Fax: 410-706-2512; E-mail: mspeh001{at}

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