Chlorpromazine inhibits store-operated calcium entry and subsequent noradrenaline secretion in PC12 cells

Abstract

1 The effect of chlorpromazine on the store-operated Ca2+ entry activated via the phospholipase C signalling pathway was investigated in PC12 cells. 2 Chlorpromazine inhibited the sustained increase after the initial peak in the intracellular Ca2+ concentration produced by bradykinin while having no effect on the initial transient response. The inhibition was lowered by the removal of extracellular free Ca2+. However, chlorpromazine did not inhibit bradykinin-induced inositol 1,4,5-trisphosphate production. 3 Chlorpromazine inhibited the bradykinin-induced noradrenaline secretion in a concentration-dependent manner (IC50: 24+/-5 muM, n = 3). 4 To test for a direct effect of chlorpromazine on store-operated Ca2+ entry, thapsigargin, an inhibitor of microsomal Ca2+-ATPase, was used to induce store-operated Ca2+ entry in PC12 cells. Chlorpromazine reduced the thapsigargin-induced sustained Ca2+ level (IC50: 24 +/- 2 muM, n = 3), and the inhibition also occluded the inhibitory action of 1-[-[3-(4-methoxyphenyl) propoxyl-4methoxyphenyl]-1H-imidazole hydrochloride (SK&F96365). 5 The results suggest that chlorpromazine negatively modulates the store-operated Ca2+ entry activated subsequent to PLC activation.