Structural determinants and significance of regulation of electrogenic Na+-HCO 3 − cotransporter stoichiometry

Abstract

Na+-HCO[Formula: see text]cotransporters play an important role in intracellular pH regulation and transepithelial HCO[Formula: see text] transport in various tissues. Of the characterized members of the HCO[Formula: see text]transporter superfamily, NBC1 and NBC4 proteins are known to be electrogenic. An important functional property of electrogenic Na+-HCO[Formula: see text] cotransporters is their HCO[Formula: see text]:Na+ coupling ratio, which sets the transporter reversal potential and determines the direction of Na+-HCO[Formula: see text] flux. Recent studies have shown that the HCO[Formula: see text]: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 HCO[Formula: see text]: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 HCO[Formula: see text]-transporting epithelia with an efficient mechanism for modulating the direction of Na+-HCO[Formula: see text] flux through the cotransporter.