MECHANISM OF RENAL NA/DICARBOXYLATE TRANSPORT

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The focus of the current proposal is to characterize at the molecular level the Na+/dicarboxylate cotransporters of the renal proximal tubule. These transporters are important to the function of the kidney in their reabsorption of Krebs cycle intermediates, and play a role in acid-base balance and organic anion excretion. The brush border Na+/dicarboxylate cotransporter has been implicated in the development of kidney stones by its regulation of urinary citrate concentrations. The principal investigator has recently cloned and sequenced a rabbit renal Na+/dicarboxylate cotransporter, NaDC-1 and the human homolog, hNaDC-1. NaDC-1 appears to correspond to the low affinity Na+/dicarboxylate cotransporter of the brush border membrane. The first specific aim of this study is to characterize the transport properties and tissue distribution of NaDC-1 and hNaDC-1. The second specific aim will address the hypothesis that acute regulation of transporter function occurs at the protein level, possibly by phosphorylation. The third specific aim is to clone and sequence the high affinity Na+/dicarboxylate cotransporter found on the renal proximal tubule basolateral membrane. The fourth specific aim will test the hypothesis that the secondary structure of NaDC-1 has eight transmembrane domains. The fifth specific aim will test the hypothesis that histidines are involved in substrate binding by NaDC-1, and that chimeras between NaDC-1 and related transporters can provide information on domains important to substrate recognition and binding. These studies should provide fundamental information on the functional properties of this family of sodium-dependent transporters, and on the physiological role of these transporters in the kidney.