We have investigated the role of endothelin-3 (ET-3) in the stimulus-secretion coupling mechanism in rat pheochromocytoma PC12 cells. ET-3 (10-100 nM) evoked both dopamine (DA) release and an increase in intracellular Ca2+ concentration ([Ca]i). The ET-3-evoked DA release was partially inhibited by pretreatment with pertussis toxin (PTX; 2 ng/nl, 20 h). The release was also attenuated by the voltage-gated Ca channel (VGC) blockers Cd2+ (300 μM) or nicardipine (30 μM) and was completely abolished when external Ca2+ was removed. ET-3-evoked [Ca]i increase was attenuated by the application of these VGC blockers and by pretreatment with PTX, and was abolished by removal of extracellular Ca2+. Removal of external Na+ had no effect on either response. In light of these findings, we conclude that ET-3 evokes both DA release and an increase in [Ca]i by a mechanism which involves the activation of PTX-sensitive VGCs and the resultant influx of Ca2+.
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