NBCe1-B, a major splice variant of the electrogenic Na+-HCO3-cotransporter (NBCe1) fulfills basic cellular functions including regulation of intracellular pH and epithelial HCO3- secretion. However, its cellular regulatory mechanism still remains elusive. Here, we provide evidence for the first time that NBCe1-B activity can be controlled by intracellular Mg2+ (Mg-i(2+)), the physiologically most abundant intracellular divalent cation. Using the whole-cell patch-clamp technique, we found that recombinant NBCe1-B currents expressed in HEK293 and NIH3T3 cells were inhibited voltage-independently by Mg-i(2+) in a concentration-dependent manner (K-i approximate to 0.01 mM). The Mg-i(2+) inhibition was partially relieved by truncation of the NBCe1-B specific N-terminal region (K-i approximate to 0.3 mM), and was also observed for native electrogenic Na+-HCO3- cotransporter current in bovine parotid acinar cells that endogenously express NBCe1-B (K-i approximate to 1 mM). These results suggest that Mg2+ may be a cytosolic factor that limits intrinsic cotransport activity of NBCe1-B in mammalian cells. (C) 2008 Elsevier Inc. All Fights reserved.