Molecular Cloning, Chromosomal Localization, Tissue Distribution, and Functional Expression of the Human Pancreatic Sodium Bicarbonate Cotransporter

Abstract

We report the cloning, sequence analysis, tissue distribution, functional expression, and chromosomal localization of the human pancreatic sodium bicarbonate cotransport protein (pancreatic NBC (pNBC)). The transporter was identified by searching the human expressed sequence tag data base. An I.M.A.G.E. clone W39298 was identified, and a polymerase chain reaction probe was generated to screen a human pancreas cDNA library. pNBC encodes a 1079-residue polypeptide that differs at the N terminus from the recently cloned human sodium bicarbonate cotransporter isolated from kidney (kNBC) (Burnham, C. E., Amlal, H., Wang, Z., Shull, G. E., and Soleimani, M. (1997) J. Biol. Chem. 272, 19111-19114). Northern blot analysis using a probe specific for the N terminus of pNBC revealed an ϳ7.7-kilobase transcript expressed predominantly in pancreas, with less expression in kidney, brain, liver, prostate, colon, stomach, thyroid, and spinal chord. In contrast, a probe to the unique 5 region of kNBC detected an ϳ7.6-kilobase transcript only in the kidney. In situ hybridization studies in pancreas revealed expression in the acini and ductal cells. The gene was mapped to chromosome 4q21 using fluorescent in situ hybridization. Expression of pNBC in Xenopus laevis oocytes induced sodium bicarbonate cotransport. These data demonstrate that pNBC encodes the sodium bicarbonate cotransporter in the mammalian pancreas. pNBC is also expressed at a lower level in several other organs, whereas kNBC is expressed uniquely in kidney.

Functional characterization of NBC4: a new electrogenic sodium-bicarbonate cotransporter

“…pNBC1 transcripts have also been detected in many organs, indicating the ubiquitous expression of this transporter (1). The second known NBC1 protein variant, kNBC1, is more restricted in its tissue expression and has thus far been detected in kidney and eye (8,29).…”

“…kNBC1 mediates the majority of basolateral HCO 3 Ϫ efflux in the renal proximal tubule (2,9,26,29). pNBC1 is highly expressed in pancreas and various other tissues (1,8,14,20,21). An electroneutral NBC, NBC3 in humans (rat ortholog NBCn1) mediates Cl Ϫ -independent and stilbene-insensitive Na ϩ -HCO 3 Ϫ cotransport in various tissues (10,20,22,25).…”

IRBIT, an inositol 1,4,5-trisphosphate receptor-binding protein, specifically binds to and activates pancreas-type Na + /HCO 3 − cotransporter 1 (pNBC1)

“…In pancreas, pNBC1 is thought to mediate HCO 3 Ϫ uptake into pancreatic duct cells in response to hormonal stimulation (3). However, expression of kNBC1 is almost completely limited to the kidney (9), where it mediates constitutive HCO 3 Ϫ exit from proximal tubules (3). However, the molecular mechanism underlying these different physiological roles of NBC1 variants has not been elucidated.…”

“…Despite their high sequence similarity, these NBC1 variants are thought to have quite different physiological roles. pNBC1 is predominantly expressed in the pancreas, and lower levels are expressed in several organs, including the brain and eyes (9,13). In pancreas, pNBC1 is thought to mediate HCO 3 Ϫ uptake into pancreatic duct cells in response to hormonal stimulation (3).…”

Sodium-Coupled Bicarbonate Transporters

“…Others subsequently described inwardly directed electrogenic Na/HCO 3 cotransporters in several mammalian cells, including pancreatic duct cells [20,21]; we functionally identified it in rat astrocytes [22]. Kurtz [23], as well as our group [24], cloned the "pancreatic" NBCe ( Figure 2: NBCe1-B), which is a splice variant of NBCe1-A. We also cloned a "brain" NBCe ( Figure 2: NBCe1-C) [25], and showed that an NBCe protein is present in astrocytes [25] and the basolateral membrane of pancreatic duct [26].…”