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J. Biol. Chem., Vol. 282, Issue 48, 35125-35132, November 30, 2007

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Enhanced Formation of a Transport Metabolon in Exocrine Cells of Nhe1^–/– Mice^*

Mireya Gonzalez-Begne¹, Tetsuji Nakamoto¹, Ha-Van Nguyen¹, Andrew K. Stewart, Seth L. Alper, and James E. Melvin²

From the Center for Oral Biology, University of Rochester Medical Center, Rochester, New York 14642, the Molecular and Vascular Medicine Unit and the Renal Division, Beth Israel Deaconess Medical Center, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215

Cl^- influx across the basolateral membrane is a limiting step in fluid production in exocrine cells and often involves functionally linked (Ae) and Na⁺/H⁺ (Nhe) exchange mechanisms. The dependence of this major Cl^- uptake pathway on Na⁺/H⁺ exchanger expression was examined in the parotid acinar cells of Nhe1^-/- and Nhe2^-/- mice, both of which exhibited impaired fluid secretion. No change in exchanger activity was detected in Nhe2-deficient mice. Conversely, exchanger activity increased nearly 4-fold in Nhe1-deficient mice, despite only minimal or any change in mRNA and protein levels of the anion exchanger Ae2. Acetazolamide completely blocked the increase in exchanger activity in Nhe1-null mice suggesting that increased anion exchange required carbonic anhydrase activity. Indeed, the parotid glands of Nhe1^-/- mice expressed higher levels of carbonic anhydrase 2 (Car2) polypeptide. Moreover, the enhanced exchange activity was accompanied by an increased abundance of Car2·Ae2 complexes in the parotid plasma membranes of Nhe1^-/- mice. Anion exchanger activity was also significantly reduced in Car2-deficient mice, consistent with an important role of a putative Car2·Ae2 transport metabolon in parotid exocrine cell function. Increased abundance of this transport metabolon is likely one of the multiple compensatory changes in the exocrine parotid gland of Nhe1^-/- mice that together attenuate the severity of in vivo electrolyte and acid-base balance perturbations.

Received for publication, August 29, 2007 , and in revised form, September 17, 2007.

^* This work was supported by National Institutes of Health Grants DE08921 and DE09692 (to J. E. M.) and DK43495 (to S. L. A.). 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 These authors contributed equally to this work.

² To whom correspondence should be addressed: Center for Oral Biology, University of Rochester Medical Center, Box 611, 601 Elmwood Ave., Rochester, NY 14642. Fax: 585-276-0190; E-mail: james_melvin{at}urmc.rochester.edu.

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