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Originally published In Press as doi:10.1074/jbc.M003753200 on May 30, 2000

J. Biol. Chem., Vol. 275, Issue 35, 26720-26726, September 1, 2000
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Severe Impairment of Salivation in Na+/K+/2Clminus Cotransporter (NKCC1)-deficient Mice*

Richard L. EvansDagger §**, Keerang ParkDagger §, R. James Turner||, Gene E. Watson**, Ha-Van NguyenDagger , Matthew R. DennettDagger , Arthur R. HandDagger Dagger , Michael Flagella§§, Gary E. Shull§§, and James E. MelvinDagger **¶¶

From the Dagger  Center for Oral Biology, Aab Institute of Biomedical Sciences and the ** Eastman Department of Dentistry, University of Rochester Medical Center, Rochester, New York 14642, the || NIDCR, Gene Therapy & Therapeutics Branch, National Institutes of Health, Bethesda, Maryland 20892, the Dagger Dagger  Department of Pediatric Dentistry, University of Connecticut, Farmington, Connecticut 06030, and the §§ Department of Molecular Genetics, Biochemistry & Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

The salivary fluid secretory mechanism is thought to require Na+/K+/2Cl- cotransporter-mediated Cl- uptake. To directly test this possibility we studied the in vivo and in vitro functioning of acinar cells from the parotid glands of mice with targeted disruption of Na+/K+/2Cl- cotransporter isoform 1 (Nkcc1), the gene encoding the salivary Na+/K+/2Cl- cotransporter. In wild-type mice NKCC1 was localized to the basolateral membranes of parotid acinar cells, whereas expression was not detected in duct cells. The lack of functional NKCC1 resulted in a dramatic reduction (>60%) in the volume of saliva secreted in response to a muscarinic agonist, the primary in situ salivation signal. Consistent with defective Cl- uptake, a loss of bumetanide-sensitive Cl- influx was observed in parotid acinar cells from mice lacking NKCC1. Cl-/ HCO3- exchanger activity was increased in parotid acinar cells isolated from knockout mice suggesting that the residual saliva secreted by mice lacking NKCC1 is associated with anion exchanger-dependent Cl- uptake. Indeed, expression of the Cl-/ HCO3- exchanger AE2 was enhanced suggesting that this transporter compensates for the loss of functional Na+/K+/2Cl- cotransporter. Furthermore, the ability of the parotid gland to conserve NaCl was abolished in NKCC1-deficient mice. This deficit was not associated with changes in the morphology of the ducts, but transcript levels for the alpha -, beta -, and gamma -subunits of the epithelial Na+ channel were reduced. These data directly demonstrate that NKCC1 is the major Cl- uptake mechanism across the basolateral membrane of acinar cells and is critical for driving saliva secretion in vivo.

* This work was supported in part by National Institutes of Health Grants DK50594 (to G. E. S.) and DE13539, DE08921, and DE09692 (to J. E. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this project.

Present address: Unilever Research, Port Sunlight Laboratory, Quarry Road East, Bebington, Wirral CH63 3JW, UK. E-mail: Richard.Evans@Unilever.com.

¶¶ To whom correspondence should be addressed: Center for Oral Biology, University of Rochester, Medical Center Box 611, 601 Elmwood Ave., Rochester, NY 14642. Tel.: 716-275-3444; Fax: 716-473-2679; E-mail: james_melvin@urmc.rochester.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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