title: [Pharmacological properties of novel TRPC channel inhibitors].
abstract: Ca(2+) 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 Ca(2+) 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 Ca(2+) oscillation regulated by TRPC3-mediated Ca(2+) 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.
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kiyonaka
authors.forename: Kenta
authors.initials: K
authors.lastname: Kato
authors.forename: Motohiro
authors.initials: M
authors.lastname: Nishida
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D006332:Cardiomegaly / Q000188:drug therapy / Q000235:genetics; D015195:Drug Design; D006801:Humans; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*
chemical_list: D011720:Pyrazoles; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D002118:Calcium