receptorsendothelin

Endothelin receptors are a family of G protein–coupled receptors that bind endothelins, especially endothelin-1 (ET-1). The two principal subtypes are ETA and ETB, encoded by the genes EDNRA and EDNRB, respectively. Endothelin peptides are among the most potent endogenous vasoconstrictors and are mainly produced by vascular endothelial cells, with ET-1 being the predominant circulating form.

ETA receptors are primarily found on vascular smooth muscle cells and mediate vasoconstriction and cell proliferation when activated. ETB receptors are expressed on endothelial cells, where activation stimulates the release of vasodilators such as nitric oxide and prostacyclin, contributing to vasodilation; ETB receptors on some smooth muscle cells can also cause vasoconstriction.

Signaling of the endothelin receptors is mainly through Gq/11 proteins leading to phospholipase C activation, inositol trisphosphate and diacylglycerol generation, calcium mobilization, and protein kinase C activation. ETB may also couple to Gi proteins. Receptors may be internalized upon activation and participate in desensitization processes.

Endothelin signaling is involved in vascular tone, remodeling, and organ perfusion. Dysregulation is linked to conditions such as pulmonary arterial hypertension, systemic hypertension, and heart failure. The endothelin system is a target for pharmacotherapy; endothelin receptor antagonists (ERAs) include bosentan (nonselective ETA/ETB), ambrisentan (ETA-selective), and macitentan (dual). These agents reduce pulmonary vascular resistance and improve exercise capacity in PAH but can cause liver function abnormalities and are teratogenic.

In synthesis, endothelin receptors mediate opposing vascular responses depending on subtype and cellular context; ETA promotes vasoconstriction while ETB can promote vasodilation via endothelial mediators. Pharmacologic modulation of these receptors is an established strategy in treating certain cardiovascular diseases.