Characterization of Different Isoforms of the K+-dependent Na+- Ca2+ Exchangers: A Look into Ca2+ Coordination and Functional Consequences of Mutations Associated with Different Genetic Diseases

Abstract

K+-dependent Na+-Ca2+ exchangers (NCKXs) belong to the Solute Carrier 24 gene family of membrane transporters. Five different exchangers have been identified in humans and contribute to many biological processes including vision, enamel maturation, Melanocortin-4-receptor-dependent satiety, olfaction and skin pigmentation. Here, I examined the differences in cation coordination of NCKX1-4 and tested the effect of single residue substitutions in the α-repeats on Ca2+ affinity in NCKX2. In addition, I investigated the functional consequences of mutations in different NCKX genes associated with genetic diseases. I measured NCKX-mediated Ca2+ transport activity of WT and mutant NCKX proteins while manipulating external or internal ion concentrations. I concluded that the differences observed among these exchangers do not explain the variation in their tissue distribution. Also, 13 single residue substitutions significantly lowered Ca2+ affinity in NCKX2. Moreover, the functional data presented about the mutations associated with genetic diseases support that the genetic analysis describing these mutations.