Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 282, Issue 12, Pages 9042-9052Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M607041200
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Funding
- NCRR NIH HHS [T32-RR-07004] Funding Source: Medline
- NHLBI NIH HHS [HL61974] Funding Source: Medline
- NIDDK NIH HHS [DK50594, DK67749, DK57552, DK48816] Funding Source: Medline
- NIEHS NIH HHS [ES06096] Funding Source: Medline
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The NBC1 Na+/HCO3- 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 HCO3- 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 HCO3- 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+, hyperaldosteronism, splenomegaly, abnormal dentition, intestinal obstructions, and death before weaning. Intracellular pH (pH;) 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 HCO3-, 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 HCO3- revealed a sharp decrease in both cAMP-stimulated HCO3- secretion and SITS-sensitive current in NBC1(-/-) proximal colon. These results are consistent with the known function of NBC1 in HCO3- absorption in the kidney and demonstrate that NBC1 activity is a component of the basolateral mechanisms for HCO3- uptake during cAMP-stimulated anion secretion in the proximal colon.
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