A Pyrazole Derivative Potently Inhibits Lymphocyte Ca 2+ Influx and Cytokine Production by Facilitating Transient Receptor Potential Melastatin 4 Channel Activity
2006; American Society for Pharmacology and Experimental Therapeutics; Volume: 69; Issue: 4 Linguagem: Inglês
10.1124/mol.105.021154
ISSN1521-0111
AutoresRyuichi Takezawa, Henrique Cheng, Andreas Beck, Jun Ishikawa, Pierre Launay, Hirokazu Kubota, Jean‐Pierre Kinet, Andrea Fleig, Toshimitsu Yamada, Reinhold Penner,
Tópico(s)Piperaceae Chemical and Biological Studies
Resumo3,5-Bis(trifluoromethyl)pyrazole derivative (BTP2) or N -[4-3, 5-bis(trifluromethyl)pyrazol-1-yl]-4-methyl-1,2,3-thiadiazole-5-carboxamide (YM-58483) is an immunosuppressive compound that potently inhibits both Ca 2+ influx and interleukin-2 (IL-2) production in lymphocytes. We report here that BTP2 dosedependently enhances transient receptor potential melastatin 4 (TRPM4), a Ca 2+ -activated nonselective (CAN) cation channel that decreases Ca 2+ influx by depolarizing lymphocytes. The effect of BTP2 on TRPM4 occurs at low nanomolar concentrations and is highly specific, because other ion channels in T lymphocytes are not significantly affected, and the major Ca 2+ influx pathway in lymphocytes, I CRAC , is blocked only at 100-fold higher concentrations. The efficacy of BTP2 in blocking IL-2 production is reduced approximately 100-fold when preventing TRPM4-mediated membrane depolarization, suggesting that the BTP2-mediated facilitation of TRPM4 channels represents the major mechanism for its immunosuppressive effect. Our results demonstrate that TRPM4 channels represent a previously unrecognized key element in lymphocyte Ca 2+ signaling and that their facilitation by BTP2 supports cell membrane depolarization, which reduces the driving force for Ca 2+ entry and ultimately causes the potent suppression of cytokine release.
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