TRPCチャネルを標的とした新規Ca2+拮抗薬の創製

概要

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Ca2+ signals control diverse cellular processes, ranging from ubiquitous activities like gene expression to tissue specific responses such as lymphocyte activation and cardiac diseases. TRPC channels control Ca2+ influxes that induce diverse cellular processes upon stimulation of plasma membrane receptors coupled to phospholipase C (PLC). Invention of subtype-specific inhibitors for TRPCs is crucial for distinction of respective TRPC channels that play particular physiological roles in native systems. Here, we identify a novel pyrazole compound (Pyr3) which selectively inhibits TRPC3 channels. Structure-function relationship studies of pyrazole compounds showed that the trichloroacrylic amide group is important for the TRPC3 selectivity of Pyr3. Electrophysiological and photoaffinity labeling experiments reveal a direct action of Pyr3 on the TRPC3 protein. In B lymphocytes, Pyr3 eliminated the B cell receptor-induced Ca2+ oscillation regulated by TRPC3-mediated Ca2+ influx. In the cardiac system, Pyr3 attenuates activation of nuclear factor of activated T cells and hypertrophic growth in myocytes and pressure overload-induced hypertrophy in vivo. Thus, the TRPC3-selective inhibitor Pyr3 is useful for treatments of TRPC3-mediated diseases and for clarification of crucial and widespread functions of TRPC3 as well.