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 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.
Takezawa
Ryuichi
R
Laboratory of Cell and Molecular Signalling, Center for Biomedical Research, The Queen's Medical Center, 1301 Punchbowl St., UHT 8, Honolulu, HI 96813, USA.
Cheng
Henrique
H
Beck
Andreas
A
Ishikawa
Jun
J
Launay
Pierre
P
Kubota
Hirokazu
H
Kinet
Jean-Pierre
JP
Fleig
Andrea
A
Yamada
Toshimitsu
T
Penner
Reinhold
R
D000813:Anilides / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis*; D017136:Ion Transport; D019169:Jurkat Cells; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D050053:TRPM Cation Channels / Q000187:drug effects* / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology*
C476308:4-methyl-4'-(3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl)-1,2,3-thiadiazole-5-carboxanilide; D000813:Anilides; D007376:Interleukin-2; D050053:TRPM Cation Channels; D013830:Thiadiazoles; D002118:Calcium