[Functional analysis of Na+/Ca2+ exchanger using novel drugs and genetically engineered mice]

The Na+/Ca2+ exchanger (NCX) is an ion transporter that exchanges Na+ and Ca2+ in either Ca2+ efflux or Ca2+ influx mode, depending on the ion gradients across the plasma membrane and the membrane potential. In heart, smooth muscle cells, neurons, and nephron cells, this exchanger is thought to play an important role in the regulation of intracellular Ca2+ concentration. We aim at clarifying the function and pathologic state of the exchanger by developing NCX inhibitors and NCX-engineered mice as experimental tools, and finally establishing a novel therapeutic method using the exchanger as a molecular target. First, we present the pharmacological profiles and the molecular mechanism of NCX inhibitors (KB-R7943, SEA0400, SN-6) recently developed. Our results suggest that these NCX inhibitors preferentially block the Ca2+ influx mode rather than the Ca2+ efflux mode. Further mutational analysis reveals that these NCX inhibitors have different interaction domains in the exchanger molecule. Secondly, we present that heterozygous NCX1-knockout mice are useful as a low NCX1-expressing animal model. From comparative experiments with heterozygous and wild-type mice and pharmacological experiments of the NCX inhibitors, we provided an evidence that NCX1 functionally contributes to maintaining the vascular tension.