Mechanism of endothelin-1-(1-31)-induced calcium signaling in human coronary artery smooth muscle cells.
We have found that human chymase produces a 31-amino acid endothelin [ET-1-(1-31)] from the 38-amino acid precursor (Big ET-1). We examined the mechanism of synthetic ET-1-(1-31)-induced intracellular Ca2+ signaling in cultured human coronary artery smooth muscle cells. ET-1-(1-31) increased the intracellular free Ca2+ concentration ([Ca2+]i) in a concentration-dependent manner (10(-14)-10(-10) M). This ET-1-(1-31)-induced [Ca2+]i increase was not affected by phosphoramidon, Bowman-Birk inhibitor, and thiorphan. The ET-1-(1-31)-induced [Ca2+]i increase was not influenced by removal of extracellular Ca2+ but was inhibited by thapsigargin. ET-1-(1-31) at 10(-12) M did not cause Ca2+ influx, whereas 10(-7) M ET-1-(1-31) evoked marked Ca2+ influx, which was inhibited by nifedipine. ET-1-(1-31) also increased inositol trisphosphate formation. These results suggest that the ET-1-(1-31)-induced [Ca2+]i increase at relatively low concentrations is attributable to the release of Ca2+ from inositol trisphosphate-sensitive intracellular stores, whereas Ca2+ influx into the cells evoked by high concentration of ET-1-(1-31) probably occurs through voltage-dependent Ca2+ channels. We concluded that the physiological activity of ET-1-(1-31) may be attributable to Ca2+ mobilization from intracellular stores rather than influx of Ca2+ from extracellular space.
Inui
D
D
Department of Pharmacology, The University of Tokushima School of Medicine, Tokushima 770-8503, Japan.
Yoshizumi
M
M
Okishima
N
N
Houchi
H
H
Tsuchiya
K
K
Kido
H
H
Tamaki
T
T
D001158:Arteries / Q000166:cytology / Q000187:drug effects; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects*; D019332:Endothelin-1 / Q000378:metabolism / Q000031:analogs & derivatives; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000494:pharmacology*; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis; D007425:Intracellular Membranes / Q000378:metabolism; D008666:Metalloendopeptidases; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D009994:Osmolar Concentration; D010446:Peptide Fragments / Q000494:pharmacology*
D019332:Endothelin-1; D016232:Endothelins; D007295:Inositol Phosphates; D010446:Peptide Fragments; C114932:endothelin-1 (1-31); D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; D002118:Calcium