2009年3月
Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
- 巻
- 106
- 号
- 13
- 開始ページ
- 5400
- 終了ページ
- 5405
- 記述言語
- 英語
- 掲載種別
- DOI
- 10.1073/pnas.0808793106
- 出版者・発行元
- NATL ACAD SCIENCES
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.
- リンク情報
-
- DOI
- https://doi.org/10.1073/pnas.0808793106
- J-GLOBAL
- https://jglobal.jst.go.jp/detail?JGLOBAL_ID=200902250460008393
- PubMed
- https://www.ncbi.nlm.nih.gov/pubmed/19289841
- Web of Science
- https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000264790600080&DestApp=WOS_CPL
- ID情報
-
- DOI : 10.1073/pnas.0808793106
- ISSN : 0027-8424
- J-Global ID : 200902250460008393
- PubMed ID : 19289841
- Web of Science ID : WOS:000264790600080