Specificity of the Na⁺-dependent monocarboxylic acid transport pathway in rabbit renal brush border membranes

The substrate specificity of a Na⁺-dependent transport pathway for l-lactate was studied in rabbit renal brush border membrane vesicles. J_max for l-lactate transport was unaffected by the presence of a fixed concentration of two different short-chain monocarboxylic acids, while the apparent K_t(K_a) for l-lactate increased, and this is compatible with competitive inhibition. The inhibitor constants ("K_i"'s) for the transport pathway for the two solutes examined closely corresponded to the respective "K_i"'s derived from a Dixon plot. A broad range of compounds were then tested as potential inhibitors of l-lactate transport, and the "K_i"'s thereby derived yielded specific information regarding optimal substrate recognition by the carrier. A single carboxyl group is an absolute requirement for recognition, and preference is given to 3 to 6 C chain molecules. Addition of ketone, hydroxyl and, particularly, amine groups at any carbon position, diminishes substrate-carrier interaction. Intramolecular forces, notably the inductive effects of halogens, may play a role in enhancing substrate-carrier interaction; however, no correlation was found between pK_a and "K_i" for the substrates examined. We conclude that a separate monocarboxylic acid transport pathway, discrete from either the d-glucose, α or β neutral amino-acid, or dicarboxylic acid carriers, exists in the renal brush border, and this handles a broad range of monocarboxylates.