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First published on January 11, 2006; DOI: 10.1124/mol.105.021154

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Received for publication November 29, 2005.
Revised January 5, 2006.
Accepted for publication January 10, 2006.

A pyrazole derivative potently inhibits lymphocyte Ca2+ influx and cytokine production by facilitating TRPM4 channel activity

Ryuichi Takezawa 1, Henrique Cheng 2, Andreas Beck 3, Jun Ishikawa 4, Pierre Launay 5, Hirokazu Kubota 4, Jean-Pierre Kinet 5, Andrea Fleig 3, Toshimitsu Yamada 4, Reinhold Penner 3*

1 Yamanouchi Pharmaceutical 2 University of South Florida 3 The Queen's Medical Center 4 Yamanouchi Pharmaceuticals 5 Harvard Medical School

* Address correspondence to: E-mail: rpenner{at}hawaii.edu

Abstract

3,5-bis(trifluoromethyl)pyrazole derivative (BTP2 or YM-58483) is an immunosuppressive compound that potently inhibits both Ca2+ influx and IL-2 production in lymphocytes. We here report that BTP2 dose-dependently enhances TRPM4, a Ca2+-Activated Nonselective (CAN) cation channel, which decreases Ca2+ influx by depolarizing lymphocytes. The effect of BTP2 on TRPM4 occurs at low nanomolar concentrations and is highly specific, since 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 to block IL-2 production is reduced about 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.


Key words: Ion channel regulation, Calcium (G Protein Coupled Signals)


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