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

Laboratory of Cell and Molecular Signaling, Center for Biomedical Research at the Queen's Medical Center and John A. Burns School of Medicine at the University of Hawaii, Honolulu, Hawaii (H.C., A.B., A.F., R.P.); Inflammation Research, Pharmacology Laboratories (R.T., J.I., T.Y.), Medicinal Chemistry Research II, Chemistry Laboratories (H.K.), Institute for Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan; and Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts (P.L., J.-P.K.)

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, 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 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.

Address correspondence to: Dr. Reinhold Penner, Center for Biomedical Research, The Queen's Medical Center, 1301 Punchbowl St., UHT 8, Honolulu, HI 96813. E-mail: rpenner{at}hawaii.edu

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