Chloroquine inhibits Ca ²⁺ permeable ion channels-mediated Ca ²⁺ signaling in primary B lymphocytes

Abstract

Background

Chloroquine, a bitter tastant, inhibits Ca ²⁺ signaling, resulting in suppression of B cell activation; however, the inhibitory mechanism remains unclear.

Results

In this study, thapsigargin (TG), but not caffeine, induced sustained intracellular Ca ²⁺ increases in mouse splenic primary B lymphocytes, which were markedly inhibited by chloroquine. Under Ca ²⁺-free conditions, TG elicited transient Ca ²⁺ increases, which additionally elevated upon the restoration of 2 mM Ca ²⁺. The former were from release of intracellular Ca ²⁺ store and the latter from Ca ²⁺ influx. TG-induced release was inhibited by 2-APB (an inhibitor of inositol-3-phosphate receptors, IP ₃Rs) and chloroquine, and TG-caused influx was inhibited by pyrazole (Pyr3, an inhibitor of transient receptor potential C3 (TRPC3) and stromal interaction molecule (STIM)/Orai channels) and chloroquine. Moreover, chloroquine also blocked Ca ²⁺ increases induced by the engagement of B cell receptor (BCR) with anti-IgM.

Conclusions

These results indicate that chloroquine inhibits Ca ²⁺ elevations in splenic B cells through inhibiting Ca ²⁺ permeable IP ₃R and TRPC3 and/or STIM/Orai channels. These findings suggest that chloroquine would be a potent immunosuppressant.