Endothelin Receptors: form and function.

The endothelin peptides act as a result of binding seven transmembrane spanning, G-protein coupled receptors. The first described receptor, ETA, exhibits greater affinity for ET-1 compared to ET-3, and is expressed on various cells including vascular smooth muscle and cardiomyocytes. This receptor triggers the cardiac hypertrophic response to ET-1, and the pressor and vasoconstricting effects of this ligand. ETA signals through Cai++ mobilization following PLC hydrolysis and IP3 generation. This underlies cyclosporine-induced hypertension and nephrotoxicity. Activation of protein kinase C and MAP kinase contribute to ET-1 induced vascular smooth muscle proliferation. Hydrolysis of phospholipases A and D lead to pulmonary prostanoid formation and bronchoconstriction. In contrast, this receptor can inhibit cardiac chloride, L-type Ca++, and some K+ channels, protecting against catecholamine-induced arrhythmia. A second receptor, ETB, is expressed on endothelial and vascular smooth muscle cells, and binds ET-1 and ET-3 comparably. This receptor links the EST to the generation of nitric oxide, prostacyclin formation, and vasodilatation. In human coronaries, ETB may contribute to vasoconstriction. This protein appears to be critical for neural crest development. A third receptor, ETC, has been cloned from frog melanophores, and is highly responsive to ET-3. No comparable mammalian receptor has yet been identified.