Signal transduction mechanisms mediating the vascular actions of endothelin.
Endothelin (ET)-1, an endothelium-derived vasoactive polypeptide encoded in the human genome, is the most potent vasoconstrictor identified to date. In addition to its acute role in modulating vascular smooth muscle tone, ET-1 also plays a critical role in the long-term control of cellular growth within the vasculature and thus, modulates the chronic remodeling of the vascular tree. In order to produce such a diverse range of biological responses, this peptide is able to activate numerous distinct effector systems including phospholipase C, phospholipase D, phospholipase A2, adenylate and guanylate cyclases and numerous cytosolic/nuclear protein kinases. These actions, mediated via an interaction with two major subtypes of cell surface seven-transmembrane receptors (ET(A) and ET(B)), are coupled to their effector systems by several distinct types of guanine nucleotide regulatory proteins (both inhibitory and stimulatory G proteins). This review describes such intercations and how distinct pharmacological agents have been used to identify the diverse signaling mechanisms utilized by the ET isopeptides.
Douglas
S A
SA
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa. 19406-0939, USA.
Ohlstein
E H
EH
D000818:Animals; D001665:Binding Sites; D001808:Blood Vessels / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology; D016232:Endothelins / Q000378:metabolism / Q000502:physiology; D004727:Endothelium / Q000502:physiology*; D004798:Enzymes / Q000378:metabolism; D006801:Humans; D017466:Receptors, Endothelin / Q000378:metabolism; D015398:Signal Transduction
D015220:Calcium Channels; D016232:Endothelins; D004798:Enzymes; D017466:Receptors, Endothelin