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J. Biol. Chem., Vol. 282, Issue 12, 9042-9052, March 23, 2007

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Colonic Anion Secretory Defects and Metabolic Acidosis in Mice Lacking the NBC1 Cotransporter^*

Lara R. Gawenis, Emily M. Bradford, Vikram Prasad, John N. Lorenz, Janet E. Simpson^¶, Lane L. Clarke^¶, Alison L. Woo, Christina Grisham, L. Philip Sanford, Thomas Doetschman, Marian L. Miller^||, and Gary E. Shull¹

From the Department of Molecular Genetics, Biochemistry, and Microbiology, Department of Cellular and Molecular Physiology, and ^||Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, and the ^¶Department of Biomedical Sciences and Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri 65211

The NBC1 cotransporter is expressed in many tissues, including kidney and intestinal epithelia. NBC1 mutations cause proximal renal tubular acidosis in humans, consistent with its role in absorption in the kidney. In intestinal and colonic epithelia, NBC1 localizes to basolateral membranes and is thought to function in anion secretion. To test the hypothesis that NBC1 plays a role in transepithelial secretion in the intestinal tract, null mutant (NBC1^-/-) mice were prepared by targeted disruption of its gene (Slc4a4). NBC1^-/- mice exhibited severe metabolic acidosis, growth retardation, reduced plasma Na⁺, hyperal-dosteronism, splenomegaly, abnormal dentition, intestinal obstructions, and death before weaning. Intracellular pH (pH_i) was not altered in cAMP-stimulated epithelial cells of NBC1^-/- cecum, but pH_i regulation during sodium removal and readdition was impaired. Bioelectric measurements of NBC1^-/- colons revealed increased amiloride-sensitive Na⁺ absorption. In Ringer solution containing both Cl^- and , the magnitude of cAMP-stimulated anion secretion was normal in NBC1^-/- distal colon but increased in proximal colon, with the increase largely supported by enhanced activity of the basolateral NKCC1 Na⁺-K⁺-2Cl^- cotransporter. Anion substitution studies in which carbonic anhydrase was inhibited and transepithelial anion conductance was limited to revealed a sharp decrease in both cAMP-stimulated secretion and SITS-sensitive current in NBC1^-/- proximal colon. These results are consistent with the known function of NBC1 in absorption in the kidney and demonstrate that NBC1 activity is a component of the basolateral mechanisms for uptake during cAMP-stimulated anion secretion in the proximal colon.

Received for publication, July 25, 2006 , and in revised form, December 14, 2006.

^* This work was supported by National Institutes of Health (NIH) Grants DK50594 and HL61974 (to G. E. S.), DK67749 (to L. R. G.), DK57552 (to J. N. L.), DK48816 (to L. L. C.), and T32-RR-07004 (to J. E. S.) and NIEHS, NIH, Grant ES06096 (to the Center for Environmental Genetics, Alvaro Puga PI). 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. of Molecular Genetics, Biochemistry, and Microbiology, 231 Albert Sabin Way, ML524, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524. Tel.: 513-558-0056; Fax: 513-558-1885; E-mail: shullge{at}ucmail.uc.edu.

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