SIGNAL-TRANSDUCTION MECHANISMS MEDIATING THE VASCULAR ACTIONS OF ENDOTHELIN

Endothelin (ET)-1, an endothelium-derived vasoactive polypeptide encod ed in the human genome, is the most potent vasoconstrictor identified to date. In addition to its acute role in modulating vascular smooth m uscle tone, ET-1 also plays a critical role in the long-term control o f cellular growth within the vasculature and thus, modulates the chron ic remodeling of the vascular tree, In order to produce such a diverse range of biological responses, this peptide is able to activate numer ous distinct effector systems including phospholipase C, phospholipase D, phospholipase A(2), adenylate and guanylate cyclases and numerous cytosolic/nuclear protein kinases. These actions, mediated via an inte raction with two major subtypes of cell surface seven-transmembrane re ceptors (ETA and ETB), are coupled to their effector systems by severa l distinct types of guanine nucleotide regulatory proteins (both inhib itory and stimulatory G proteins). This review describes such intercat ions and how distinct pharmacological agents have been used to identif y the diverse signaling mechanisms utilized by the ET isopeptides.