A Pyrazole Derivative, YM-58483, Potently Inhibits Store-Operated Sustained Ca2+ Influx and IL-2 Production in T Lymphocytes

Abstract

In nonexcitable cells, Ca2+ entry is mediated predominantly through the store depletion-dependent Ca2+ channels called store-operated Ca2+ (SOC) or Ca2+ release-activated Ca2+ channels. YM-58483, a pyrazole derivative, inhibited an anti-CD3 mAb-induced sustained Ca2+ influx in acute T cell leukemia, Jurkat cells. But it did not affect an anti-CD3 mAb-induced transient intracellular Ca2+ increase in Ca2+-free medium, nor anti-CD3 mAb-induced phosphorylation of phospholipase Cγ1. It was suggested that YM-58483 inhibited Ca2+ influx through SOC channels without affecting the TCR signal transduction cascade. Furthermore, YM-58483 inhibited thapsigargin-induced sustained Ca2+ influx with an IC50 value of 100 nM without affecting membrane potential. YM-58483 inhibited by 30-fold the Ca2+ influx through SOC channels compared with voltage-operated Ca2+ channels, while econazole inhibited both SOC channels and voltage-operated Ca2+ channels with an equivalent range of IC50 values. YM-58483 potently inhibited IL-2 production and NF-AT-driven promoter activity, but not AP-1-driven promoter activity in Jurkat cells. Moreover, this compound inhibited delayed-type hypersensitivity in mice with an ED50 of 1.1 mg/kg. Therefore, we concluded that YM-58483 was a novel store-operated Ca2+ entry blocker and a potent immunomodulator, and could be useful for the treatment of autoimmune diseases and chronic inflammation. Furthermore, YM-58483 would be a candidate for the study of capacitative Ca2+ entry mechanisms through SOC/CRAC channels and for identification of putative Ca2+ channel genes.