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

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

  • Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5400-5. doi: 10.1073/pnas.0808793106.
Shigeki Kiyonaka 1 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 Sato Itaru Hamachi Yasuo Mori
Affiliations

Affiliation

  • 1 Laboratory of Molecular Biology, Laboratory of Bioorganic Chemistry, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.
Abstract

Canonical transient receptor potential (TRPC) channels control influxes of CA(2+) 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 CA(2+) influx-dependent PLC translocation to the plasma membrane and late oscillatory phase of B cell receptor-induced CA(2+) response. Moreover, Pyr3 attenuated activation of nuclear factor of activated T cells, a CA(2+)-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.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-108465
    99.90%, TRPC3 Channel Inhibitor