Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound

Shigeki Kiyonaka, Kenta Kato, Motohiro Nishida, Kazuhiro Mio, Takuro Numaga, Yuichi Sawaguchi, Takashi Yoshida, Minoru Wakamori, Emiko Mori, Tomohiro Numata, Masakazu Ishii, Hiroki Takemoto, Akio Ojida, Kenta Watanabe, Aya Uemura, Hitoshi Kurose, Takashi Morii, Tsutomu Kobayashi, Yoji Sato, Chikara SatoItaru Hamachi, Yasuo Mori

Research output: Contribution to journalArticlepeer-review

320 Citations (Scopus)


Canonical transient receptor potential (TRPC) channels control influxes of Ca2+ and other cations 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 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 DT40 B lymphocytes, Pyr3 potently eliminated the Ca2+ influx-dependent PLC translocation to the plasma membrane and late oscillatory phase of B cell receptorinduced Ca2+ response. Moreover, Pyr3 attenuated activation of nuclear factor of activated T cells, a Ca2+-dependent transcription factor, and hypertrophic growth in rat neonatal cardiomyocytes, and in vivo pressure overload-induced cardiac hypertrophy in mice. These findings on important roles of native TRPC3 channels are strikingly consistent with previous genetic studies. Thus, the TRPC3- selective inhibitor Pyr3 is a powerful tool to study in vivo function of TRPC3, suggesting a pharmaceutical potential of Pyr3 in treatments of TRPC3-related diseases such as cardiac hypertrophy.

Original languageEnglish
Pages (from-to)5400-5405
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number13
Publication statusPublished - Mar 31 2009

All Science Journal Classification (ASJC) codes

  • General


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