Bicarbonate, along with CO2, is the major pH buffer of biological fluids. The inter-conversion of CO2 to HCO3- is mediated by family of carbonic anhydrases. Several organs specialize in the mobilization of HCO3-. The pancreatic ducts move CO2 and HCO3- from the blood into pancreatic secretions. The kidneys reabsorb massive amount of HCO3- daily (amount of NaHCO3 contained in 1 Ib of baking soda) through the glomerular flirtation of ~180 liters of plasma. To prevent a massive acidosis, the proximal tubules (PT) cells in the nephron subsequently reabsorb virtually all of HCO3-, as well as most of the filtered Na+, Cl-, and H2O. A great majority of HCO3- reabsorption occurs via trans-cellular coupling of the luminal Na-H+-exchanger 3 and Na+-H+-ATPase with the basolateral Na+-HCO3- cotransporters (NBC). Several related proteins constitute the emerging NBC family (NBC1-3) of membrane cotransporters that are found in a variety of epithelial and non-epithelial tissues, and may be tissue specific. Physiologically, NBC is electrogenic, Na+ and HCO3- dependent, Cl- independent, and inhibited by stilbenes (DIDS and SITS). The NBC family of proteins are 30-35% related to anion exchangers (AE2 and AE3; SLC4A1-SLC4A3) and display the same protein topology: (a) At least 10 TM domains with both the N and C-termini predicted to be intracellular, (b) presence of a large, glycosylated, extracellular loop between TM5 and TM6; and (c) the lysine residues are conserved at predicted DIDS-reactive sites.

NBC1 (human, rat, mouse 1035 aa, also called NBC-1A/1B, hkNBC, rkNBC, pNBC, hhNBC, SLC4A4) was initially cloned from human Kidney. NBC1 is 30-35% identical with AEs. It is strongly expressed in the kidney and pancreas.

The rat kidney NBC1 (rkNBC1; 1035 aa) is 86% identical to hkNBC1. Pancreatic NBC (pNBC/hhNBC/SLC4A5, human 1079 aa) is identical to kNBC except that it has a unique n-terminal 85 aa sequence replacing the 41-aa in kNBC. pNBC is also more widely expressed (pancreas, thyroid, heart, and brain).

NBC2 (SLC4A6; human 1018 aa), initially isolated from retina, is only 53% identical to NBC1. It is widely expressed in retinal, testis, spleen, colon, small intestine, ovary, thymus, prostate, skeletal muscle, heat, kidney, stomach, and bone marrow. It appears to be absent in pancreas and liver.

NBC3 (SLC4A?; mouse 1089 aa, human 1044 aa) has 3 three transcripts, which are expressed in a tissue specific manner (9 kb in brain, placenta, lung, liver, muscle, kidney, pancreas, stomach, thyroid, and adrenal etc). NBC3 has two variants. NBC3 is 56% identical with NBC1 and 76% with NBC2.

Functional data suggest that presence of NBC1-3 in the kidney and other tissues as judged by direction and stoichiometry of the transporter. In kidney proximal tubules, NBC activity leads to acidification (net HCO3- efflux; stoichiometry of 3 HCO3- per Na+), whereas in other tissues (liver etc) its activity leads to cellular alkanization (net HCO3- influx; stoichiometry of 2 HCO3- per Na+).

ADI has produced highly specific rabbit antibodies to NBC1-3 using peptide sequences specific to each protein.