ENDOTHELIN RECEPTORS AND CALCIUM SIGNALING

Endothelin (ET) is a potent vasoactive peptide produced by endothelial cells that elicits prolonged constriction in most smooth mascle preparations and dilation in others, Of three isopeptides, ET-1 is the only form constitutively released and may modulate vascular tone via binding to one of several receptor subtypes in smooth muscle. Activation of the ET(A) receptor is associated with pronounced vasoconstriction whereas ET(B) receptor occupation is linked to vasodilation. In addition, other subtypes of the ET(B) receptor exist, one mediating vasodilation (ET(B1)) and the other eliciting constriction (ET(B2)). An additional receptor subtype, ET(c), has been identified although its physiological significance is uncertain. Distribution of these receptors varies between species and among tissue types, although it has been generally observed that ETA receptors predominate in arterial vessels whereas ET(B) receptors predominate on the low pressure side of the circulation. In vascular smooth muscle, an increase in intracellular Ca2+ is a common feature occurring after activation of all receptor subtypes, Upon binding of ET-1 to ET(A), phospholipase C is activated and inositol triphosphate is generated, Ca2+ is then released from intracellular stores accompanied by the influx of extracellular Ca2+ and activation of the contractile machinery. The precise mechanism by which ET-1 affects intracellular Ca2+ regalation is not fully understood, but most likely involves multiple ion channels, protein kinases, and other intracellular mediators. The events coupled to non-ET(A) receptor signaling are poorly understood.