Elucdidation of physiological and pathophysiological roles of Na^+/Ca^<2+> exchanger using drug discovery and genetic engineering

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The Na^+/Ca^<2+> exchanger (NCX) is a membrane protein that exchanges 3 to 4 Na^+ ions for each Ca^<2+> ion. The mammalian NCX forms a multigene family of homologous proteins comprising three isoforms, NCX1, NCX2, and NCX3. NCX1 is highly expressed in the heart, brain, and kidney and expressed at much lower levels in many other tissues, whereas the expression of NCX2 and NCX3 is limited mainly to the brain. In this study, we tried to elucidate physiological and pathophysiological roles of NCX using NCX inhibitors and NCX-engineered mice. From characterizing NCX inhibitors, we found that KB-R7943 and SN-6 preferentially block NCX3 and NCX1, respectively, and both specifically inhibit the reverse mode of Na^+/Ca^<2+> exchange. The following analyses of NCX1/NCX3 chimeras revealed that these two inhibitors might interact with different sites on NCX molecule. More recent data have shown that the potency of NCX inhibitors is related to the extent of NCX inactivation caused by high Na^+i_1 concentration. We have reported before that NCX inhibitors can improve the ischemia/reperfusion-induced renal injury. In this study, we analyzed the ischemia/reperfusion-induced renal injury in NCX1-knockout mice (heterozygous). Expectedly, the ischemia/reperfusion-induced renal dysfunction in the heterozygous mice was markedly attenuated compared with cases in the wild-type mice. These results suggest that Ca^<2+> overload via the reverse mode of NCX1 seems to play an important role in the pathogenesis of the ischemia/reperfusion-induced renal failure.