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Molecular Pharmacology

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Research ArticleArticle

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

Ryuichi Takezawa, Henrique Cheng, Andreas Beck, Jun Ishikawa, Pierre Launay, Hirokazu Kubota, Jean-Pierre Kinet, Andrea Fleig, Toshimitsu Yamada and Reinhold Penner
Molecular Pharmacology April 2006, 69 (4) 1413-1420; DOI: https://doi.org/10.1124/mol.105.021154
Ryuichi Takezawa
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Henrique Cheng
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Andreas Beck
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Jun Ishikawa
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Pierre Launay
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Hirokazu Kubota
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Jean-Pierre Kinet
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Andrea Fleig
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Toshimitsu Yamada
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Reinhold Penner
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Abstract

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 Ca2+ influx and interleukin-2 (IL-2) production in lymphocytes. We report here that BTP2 dosedependently enhances transient receptor potential melastatin 4 (TRPM4), a Ca2+-activated nonselective (CAN) cation channel that decreases Ca2+ 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 Ca2+ influx pathway in lymphocytes, ICRAC, 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 Ca2+ signaling and that their facilitation by BTP2 supports cell membrane depolarization, which reduces the driving force for Ca2+ entry and ultimately causes the potent suppression of cytokine release.

  • Received November 24, 2005.
  • Accepted January 10, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 69 (4)
Molecular Pharmacology
Vol. 69, Issue 4
1 Apr 2006
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Research ArticleArticle

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

Ryuichi Takezawa, Henrique Cheng, Andreas Beck, Jun Ishikawa, Pierre Launay, Hirokazu Kubota, Jean-Pierre Kinet, Andrea Fleig, Toshimitsu Yamada and Reinhold Penner
Molecular Pharmacology April 1, 2006, 69 (4) 1413-1420; DOI: https://doi.org/10.1124/mol.105.021154

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Research ArticleArticle

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

Ryuichi Takezawa, Henrique Cheng, Andreas Beck, Jun Ishikawa, Pierre Launay, Hirokazu Kubota, Jean-Pierre Kinet, Andrea Fleig, Toshimitsu Yamada and Reinhold Penner
Molecular Pharmacology April 1, 2006, 69 (4) 1413-1420; DOI: https://doi.org/10.1124/mol.105.021154
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