Pharmacological Properties of Novel TRPC Channel Inhibitors
| Autor: | Kenta Kato, Yasuo Mori, Motohiro Nishida, Shigeki Kiyonaka |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Pharmacology
Phospholipase C Photoaffinity labeling Chemistry Pharmaceutical Science pyrazole compounds Cardiomegaly Stimulation Cell biology inhibitor TRPC3 Cell surface receptor Drug Design Gene expression Animals Humans Pyrazoles Myocyte Calcium Calcium Signaling transient receptor potential canonical 3 (TRPC3) Ca2+ channels TRPC TRPC Cation Channels |
| Zdroj: | YAKUGAKU ZASSHI. 130:303-311 |
| ISSN: | 1347-5231 0031-6903 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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