The mechanism of an endothelin-1-(ET-1-) induced intracellular Ca 2+ ([Ca 2+ ] i ) increase and the receptor subtype(s) responsible for this effect in single human melanocytes were studied using fura-2/AM. ET-1 induced a transient increase in [Ca 2+ ] i in a concentrationdependent manner. The transient [Ca 2+ ] i increase was followed by a sustained plateau level of [Ca 2+ ] i which was higher than the initial [Ca 2+ ] i level. IRL-1620, a specific ET-B receptor agonist, increased [Ca 2+ ] i in a dosedependent manner. BQ-788, a specific ET-B receptor antagonist, abolished the ET-1-induced [Ca 2+ ] i increase, but BQ-123, a specific ET-A receptor antagonist, failed to prevent it. U73122, an inhibitor of phospholipase C (PLC), inhibited the ET-1-induced [Ca 2+ ] i rise in a dosedependent manner. Prior depletion of intracellular Ca 2+ stores with thapsigargin, an inhibitor of Ca 2+ -ATPase of the endoplasmic reticulum, abolished the ET-1-induced Ca 2+ transient, whereas removal of extracellular Ca 2+ with EGTA eliminated the sustained rise. These results suggest that in cultured human melanocytes the binding of ET-1 to ET-B receptors and the subsequent activation of PLC mediate ET-1-induced [Ca 2+ ] i increase. The transient [Ca 2+ ] i increase is attributed to mobilization of Ca 2+ from inositol 1,4,5-trisphosphate-sensitive intracellular Ca 2+ stores, and the sustained [Ca 2+ ] i level may be related to the influx of extracellular Ca 2+ .& k w d : Key words Endothelin-1 · Endothelin B receptor · Melanocyte · IP 3 -sensitive intracellular Ca 2+ store · Fura-2 · Thapsigargin& b d y :
The mechanism of an endothelin-1- (ET-1-) induced intracellular Ca2+ ([Ca2+]i) increase and the receptor subtype(s) responsible for this effect in single human melanocytes were studied using fura-2/AM. ET-1 induced a transient increase in [Ca2+]i in a concentration-dependent manner. The transient [Ca2+]i increase was followed by a sustained plateau level of [Ca2+]i which was higher than the initial [Ca2+]i level. IRL-1620, a specific ET-B receptor agonist, increased [Ca2+]i in a dose-dependent manner. BQ-788, a specific ET-B receptor antagonist, abolished the ET-1-induced [Ca2+]i increase, but BQ-123, a specific ET-A receptor antagonist, failed to prevent it. U73122, an inhibitor of phospholipase C (PLC), inhibited the ET-1-induced [Ca2+]i rise in a dose-dependent manner. Prior depletion of intracellular Ca2+ stores with thapsigargin, an inhibitor of Ca2+-ATPase of the endoplasmic reticulum, abolished the ET-1-induced Ca2+ transient, whereas removal of extracellular Ca2+ with EGTA eliminated the sustained rise. These results suggest that in cultured human melanocytes the binding of ET-1 to ET-B receptors and the subsequent activation of PLC mediate ET-1-induced [Ca2+]i increase. The transient [Ca2+]i increase is attributed to mobilization of Ca2+ from inositol 1,4,5-trisphosphate-sensitive intracellular Ca2+ stores, and the sustained [Ca2+]i level may be related to the influx of extracellular Ca2+.
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