Endothelin receptor type A and Endothelin receptor type B (ETA and ETB)

Endothelin receptor type A (ETA) and endothelin receptor type B (ETB) are closely related members of the class A G protein-coupled receptor (GPCR) superfamily, each spanning the plasma membrane with seven transmembrane domains[4][5][6]. They are activated by endogenous endothelin peptides (ET-1, ET-2, ET-3), with ETA and ETB sharing approximately 60% sequence similarity[2]. ETA receptors are mainly localized to vascular smooth muscle cells where they mediate potent and sustained vasoconstriction, cellular proliferation, and inflammatory responses; ETB receptors are predominantly found on endothelial cells, where they promote vasodilation through nitric oxide and prostacyclin release and function in endothelin peptide clearance[5][7]. Both receptors are expressed widely in the cardiovascular system, with roles in multiple organ systems including the kidneys, lungs, brain, and tumor microenvironments[4][5]. Aberrant endothelin receptor signaling has been implicated in numerous pathologies, particularly pulmonary arterial hypertension (PAH), systemic hypertension, heart and kidney diseases, and cancer[5][7]. Several endothelin receptor antagonists are approved or in development for these indications, with selectivity for ETA or dual activity affecting clinical outcomes and safety profiles[4][5][6].

Other names

Endothelin receptor AEndothelin receptor BETARETBRETA receptorETB receptorETRAETRB

Antagonists block binding of endothelin-1/2/3 to ETA/ETB, preventing activation of G protein signaling and downstream effects such as vasoconstriction or proliferation Some antagonists are subtype-selective (e.g., ETA-selective or ETB-selective), allowing targeted modulation Inverse agonists stabilize the inactive conformation of the receptor, reducing basal activity ETB agonists can increase nitric oxide production and promote vasodilation