Interactions between Ca2+ binding domains of the Na+-Ca2+ exchanger and secondary regulation

T he Na+-Ca2+ exchanger (NCX) is a plasma membrane protein particularly abundant in cardiomyocytes where it plays a prominent role in Ca2+ extrusion. In addition to being transported, cytoplasmic Ca2+ and Na+ regulate NCX activity by activating and inhibiting ion transport, respectively. There are two Ca2+ binding domains within the exchanger, CBD1 and CBD2, which have been crystallized and detailed structural information obtained. We have recently studied the roles of residues coordinating Ca2+ in both CBD1 and CBD2. To gain further insight into NCX regulation, we investigate here the presence of possible functional interactions between the two CBDs. This study reveals the important role of CBD organization in Ca2+ regulation of the exchanger.