Ca2+ regulation in the Na+/Ca2+ exchanger features a dual electrostatic switch mechanism

Ion transport performed by the Na+/Ca2+ exchanger (NCX) is regulated via its cytosolic Ca2+-binding domains, CBD1 and CBD2, which act as sensors for intracellular Ca2+. Striking differences in the electrostatic potential of the Ca2+-bound and Ca2+-free forms turn the CBD1 and CBD2 Ca2+-binding sites into electrostatic switches similar to those of C2 domains. Binding of Ca2+ with high affinity to CBD1 induces a conformational change that is relayed to the transmembrane domain and thereby initiates Na+/Ca2+ exchange. The Ca2+ concentration at which this conformational change occurs is determined by the Ca2+ affinities of the strictly conserved CBD1 Ca2+-binding sites that are modulated by an adjacent, variable region of CBD2. In contrast, the Ca2+-binding properties of CBD2 depend on the isoform and the type of residues in the Ca2+-binding sites, encoded by a mutually exclusive exon. This second electrostatic switch, formed by CBD2, appears to be required for sustained Na+/Ca2+ exchange and may allow tailored, tissue-specific exchange activities.