A Pyrazole Derivative Potently Inhibits Lymphocyte Ca2+ Influx and Cytokine Production by Facilitating Transient Receptor Potential Melastatin 4 Channel Activity

3,5-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...

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Bibliographic Details
Published in:Molecular pharmacology 2006-04, Vol.69 (4), p.1413-1420
Main Authors: Takezawa, Ryuichi, Cheng, Henrique, Beck, Andreas, Ishikawa, Jun, Launay, Pierre, Kubota, Hirokazu, Kinet, Jean-Pierre, Fleig, Andrea, Yamada, Toshimitsu, Penner, Reinhold
Format: Article
Language:English
Subjects:
Anilides - pharmacology
Calcium - metabolism
Cell Line
Humans
Interleukin-2 - biosynthesis
Ion Transport
Jurkat Cells
Lymphocytes - drug effects
Lymphocytes - metabolism
Thiadiazoles - pharmacology
TRPM Cation Channels - drug effects
TRPM Cation Channels - metabolism
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Summary:3,5-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.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.105.021154