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J. Biol. Chem. 278 (49): 49523-49529

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Bicarbonate-regulated Adenylyl Cyclase (sAC) Is a Sensor That Regulates pH-dependent V-ATPase Recycling*

Nuria Pastor-Soler{ddagger}, Valérie Beaulieu{ddagger}, Tatiana N. Litvin§, Nicolas Da Silva{ddagger}, Yanqiu Chen§, Dennis Brown{ddagger}¶, Jochen Buck§, Lonny R. Levin§, , and Sylvie Breton{ddagger}¶||

{ddagger}Program in Membrane Biology and Renal Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, and the §Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10021

Abstract: Modulation of environmental pH is critical for the function of many biological systems. However, the molecular identity of the pH sensor and its interaction with downstream effector proteins remain poorly understood. Using the male reproductive tract as a model system in which luminal acidification is critical for sperm maturation and storage, we now report a novel pathway for pH regulation linking the bicarbonate activated soluble adenylyl cyclase (sAC) to the vacuolar H+ATPase (V-ATPase). Clear cells of the epididymis and vas deferens contain abundant V-ATPase in their apical pole and are responsible for acidifying the lumen. Proton secretion is regulated via active recycling of V-ATPase. Here we demonstrate that this recycling is regulated by luminal pH and bicarbonate. sAC is highly expressed in clear cells, and apical membrane accumulation of V-ATPase is triggered by a sAC-dependent rise in cAMP in response to alkaline luminal pH. As sAC is expressed in other acid/base transporting epithelia, including kidney and choroid plexus, this cAMP-dependent signal transduction pathway may be a widespread mechanism that allows cells to sense and modulate extracellular pH.

Received for publication August 27, 2003.

* This study was supported by National Institutes of Health Grants HD40793 (to S. B.), DK38452 (to D. B. and S. B.), DK42956 (to D. B.), HD38722 (to L. R. L.), and GM62328 and HD42060 (to J. B.) and by NIH NRSA HD08684 (to N. P.-S.). The Microscopy Core Facility of the MGH Program in Membrane Biology is additionally supported by a Center for the Study of Inflammatory Bowel Disease (CSIBD) Center Grant DK43351 and Boston Area Diabetes and Endocrinology Research Center (BADERC) Award DK57521. 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: Massachusetts General Hospital East, Renal Unit, 149 13th St., 149-8000, Charlestown, MA 02129. Tel.: 617-726-5785; Fax: 617-726-5669; E-mail: sbreton{at}receptor.mgh.harvard.edu.

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