抄録
The electrogenic Na-HCO3 cotransporter NBC1, encoded by SLC4A4, plays important roles in whole-body acid/base homeostasis and intracellular/extracellular pH regulation. NBC1 has two major spliced variants, kidney-type cotransporter kNBC1 and pancreas-type cotransporter pNBC1. kNBC1 is predominantly expressed in renal proximal tubules, where it mediates a majority of bicarbonate absorption. On the other hand, pNBC1 is more widely distributed in several tissues such as pancreas, eye, and brain, and is involved in other biological processes. Unlike kNBC1, pNBC1 is fully activated only after an IP3 receptor binding protein IRBIT binds to the N-terminal specific region of pNBC1. Furthermore, the binding of IRBIT to pNBC1 is dependent on phosphorylation status of IRBIT. Such a unique regulation of pNBC1 by IRBIT might at least partially explain diverse physiological roles of NBC1 variants in vivo. Homozygous mutations in NBC1 cause proximal renal tubular acidosis associated with ocular abnormalities (OMIM 604278). At least 50% reduction of NBC1 activity is required to induce severe acidemia. In addition to functional defects, some NBC1 mutants showed abnormal trafficking in both polarized and non-polarized cells. Interestingly, several lines of evidence suggest that defective membrane expression of NBC1 mutants in astrocytes is associated with migraine, supporting an indispensable role of NBC1 in controlling neuronal excitability. Physiological and pathophysiological roles of NBC1 in renal and extrarenal tissues will be discussed in this symposium. [J Physiol Sci. 2008;58 Suppl:S22]
