The overall aim of the project is to characterize the molecular mechanisms underlying the transcellular transport of Na, Cl and acid-base equivalents (ie. H, OH, HCO3) in the mammalian proximal tubule. One portion of the proposal will continue our efforts to analyze in detail the kinetics of the Na-H exchanger in rabbit cell microvillus (luminal) membrane vesicles. These studies will investigate the kinetics of interaction with internal H, Na, Li and NH4; the transport of NH4; Na-Li exchange; and whether the reaction mechanism is ping-pong or simultaneous. A second portion of the proposal will examine the biochemical features of the Na-H exchanger and will involve the use of group-specific reagents to identify the chemical group(s) at the cation binding site and to label the cation binding site, the development of a method for solubilizing the exchanger and reconstituting its activity in proteoliposomes, and the use of this reconstitution assay to monitor purification of the solubilized Na-H exchanger during protein separation procedures. A third portion of the project will evaluate the transport properties of the Cl-HCO3 exchanger that we have identified in dog renal microvillus membranes and will involve analyzing the possible modifier effects of H, the kinetics of interaction with internal and external Cl and HCO3, the specificity for other anions, and the specificity for inhibitors. A fourth portion of the proposal will examine the transport pathways for Cl, OH and HCO3 in basolateral membrane vesicles isolated from dog and rabbit kidneys. These experiments will screen for conductive pathways, anion exchange mechanisms, K-coupled transport processes and Na-coupled transport processes for Cl, OH and HCO3. Given the common transport mechanisms for Na, Cl, and acid-base equivalents that seem to operate in leaky epithelia, the proposed studies are relevant to understanding the physiology and pathophysiology not only of the proximal tubule but of many other epithelia as well. Moreover, the planned studies on the kinetics and biochemistry of the Na-H exchanger are highly relevant to cell physiology in general, given the important roles that Na-H exchangers in nonepithelial cells play in such important processes as intracellular pH regulation, cell volume regulation and regulation of cell proliferation.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine B Study Section (GMB)
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Yale University
Schools of Medicine
New Haven
United States
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