Cloning, characterization, and chromosomal mapping of a human electroneutral Na+-driven Cl-NCO3 exchanger

The electroneutral Na+-driven Cl-HCO3 exchanger is a key mechanism for regulating intracellular pH (pH(i)) in neurons, glia, and other cells, Here we report the cloning, tissue distribution, chromosomal location, and functional characterization of the cDNA of such a transporter (NDCBE1) from human brain (GenBank(TM) accession number AF069512). NDCBE1, which encodes 1044 amino acids, is 34% identical to the mammalian anion exchanger (AF2); similar to 50% to the electrogenic Na/HCO3 co-transporter (NBCe1) from salamander, rat, and humans; similar to 73% to mammalian electroneutral Na/HCO3 cotransporters (NBCn1); 71% to mouse NCBE; and 47% to a Na+-driven anion exchanger (NDAE1) from Drosophila, Northern blot analysis of NDCBE1 shows a robust similar to 12-kilobase signal in all major regions of human brain and in testis, and weaker signals in kidney and ovary. This human gene (SLC4A8) maps to chromosome 12q13. When expressed in Xenopus oocytes and running in the forward direction, NDCBE1 is electroneutral and mediates increases in both pH(i) and [Na+](i) (monitored with microelectrodes) that require HCO3- and are blocked by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). The pH(i) increase also requires extracellular Na+. The Na+:HCO3- stoichiometry is 1:2. Forward-running NDCBE1 mediates a Cl-36 efflux that requires extracellular Na+ and HCO3- and is blocked by DIDS. Running in reverse, NDCBE1 requires extracellular Cl-. Thus, NDCBE1 encodes a human, electroneutral Na+-driven ClHCO3 exchanger.