Structural determinants and significance of regulation of electrogenic Na+-HCO3- cotransporter stoichiometry

Na+-HCO3- cotransporters play an important role in intracellular pH regulation and transepithelial HCO3- transport in various tissues. Of the characterized members of the HCO3- transporter superfamily, NBC1 and NBC4 proteins are known to be electrogenic. An important functional property of electrogenic Na+-HCO3- cotransporters is their HCO3-:Na+ coupling ratio, which sets the transporter reversal potential and determines the direction of Na+-HCO3- flux. Recent studies have shown that the HCO3-:Na+ transport stoichiometry of NBC1 proteins is either 2: 1 or 3: 1 depending on the cell type in which the transporters are expressed, indicating that the HCO3-:Na+ coupling ratio can be regulated. Mutational analysis has been very helpful in revealing the molecular mechanisms and signaling pathways that modulate the coupling ratio. These studies have demonstrated that PKA-dependent phosphorylation of the COOH terminus of NBC1 proteins alters the transport stoichiometry. This cAMP-dependent signaling pathway provides HCO3--transporting epithelia with an efficient mechanism for modulating the direction of Na+-HCO3- flux through the cotransporter.