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Abstract
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 A<sub>2</sub>, 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<sub>a</sub> and ET<sub>B</sub>), 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.