Two C-terminal variants of NBC4, a new member of the sodium bicarbonate cotransporter family: cloning, characterization, and localization.

We report the cloning, characterization, and chromosomal assignment of a new member of the sodium bicarbonate cotransporter (NBC) family, NBC4. The NBC4 gene was mapped to chromosome 2p13 and is a new candidate gene for Alstrom syndrome. Two variants of the transporter have been isolated from human testis and heart, which differ in their C termini. NBC4a encodes a 1137-residue polypeptide and is widely expressed in various tissues, including liver, testis, and spleen. NBC4b is identical to NBC4a except that it has a 16-nucleotide insert, creating a C-terminal frame shift. NBC4b encodes a 1074-residue polypeptide and is highly expressed in heart. Amino acids 1-1046 are common to both NBC4 variants. NBC4a has two protein-interacting domains that are lacking in NBC4b: a proline-rich sequence, PPPSVIKIP (amino acids 1102-1110), and a consensus PDZ-interacting domain, SYSL (1134-1137). NBC4b lacks the stretch of charged residues present in the C terminus of NBC4a and other members of the NBC family. Unlike other members of the NBC family, both NBC4a and NBC4b have a unique glycine-rich region (amino acids 440-469). In comparison with other members of the bicarbonate transport superfamily, NBC4a and NBC4b are most similar structurally to the electrogenic sodium bicarbonate cotransporters (NBC1).