Na+/Ca2+Exchange as a Drug Target—Insights from Molecular Pharmacology and Genetic Engineering

The Na+/Ca2+ exchanger (NCX) is an ion transporter that exchanges Na+ and Ca2+ in either Ca2+-efflux or Ca2+-influx mode, depending on membrane potential and transmembrane ion gradients. In myocytes, neurons, and renal tubular cells, NCX is thought to play an important role in the regulation of intracellular Ca2+ concentration. So far the benzyloxyphenyl derivatives (KB-R7943, SEA0400, SN-6, and YM-244769) have been developed as selective NCX inhibitors. These inhibitors possess different isoform selectivities, although they have similar properties, such as Ca2+-influx mode selectivity and I1 inactivation-dependence. Site-directed mutageneses have revealed that these inhibitors possess some molecular determinants (Phe-213, Val-227, Tyr-228, Gly-833, and Asn-839) for interaction with NCX1. These benzyloxyphenyl derivatives are expected to be useful tools to study the physiological roles of NCX. Interestingly, benzyloxyphenyl NCX inhibitors effectively prevent several ischemia-reperfusion injuries and salt-dependent hypertension in animal models. Furthermore, several experiments with genetically engineered mice provide compelling evidence that these diseases are triggered by pathological Ca2+ entry through NCX1. Thus, NCX inhibitors may have therapeutic potential as novel drugs for reperfusion injury and salt-dependent hypertension.