Abstract
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 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 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.
| Original language | English |
|---|---|
| Pages (from-to) | 303-311 |
| Number of pages | 9 |
| Journal | Yakugaku Zasshi |
| Volume | 130 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 1 2010 |
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All Science Journal Classification (ASJC) codes
- Pharmacology
- Pharmaceutical Science
Cite this
Pharmacological properties of novel TRPC channel inhibitors. / Kiyonaka, Shigeki; Kato, Kenta; Nishida, Motohiro; Mori, Yasuo.
In: Yakugaku Zasshi, Vol. 130, No. 3, 01.03.2010, p. 303-311.Research output: Contribution to journal › Review article
}
TY - JOUR
T1 - Pharmacological properties of novel TRPC channel inhibitors
AU - Kiyonaka, Shigeki
AU - Kato, Kenta
AU - Nishida, Motohiro
AU - Mori, Yasuo
PY - 2010/3/1
Y1 - 2010/3/1
N2 - 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 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 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.
AB - 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 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 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=77649247811&partnerID=8YFLogxK
U2 - 10.1248/yakushi.130.303
DO - 10.1248/yakushi.130.303
M3 - Review article
C2 - 20190514
AN - SCOPUS:77649247811
VL - 130
SP - 303
EP - 311
JO - Yakugaku Zasshi
JF - Yakugaku Zasshi
SN - 0031-6903
IS - 3
ER -