EDNRA

EDNRA (ETA) is the class A GPCR that mediates endothelin-1's potent, sustained vasoconstriction in vascular smooth muscle - the dominant driver of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) and a key target in systemic hypertension, heart failure, and cancer stroma biology. ETA preferentially binds ET-1 and ET-2 with sub-nM affinity and shows >100-fold lower affinity for ET-3, distinguishing it from ETB (which binds all three equally). Approved ETA-selective and dual ETA/ETB antagonists make this one of the best-validated GPCR targets for peptide and small-molecule scaffolds in cardiovascular medicine.

EDNRA (chromosome 4q31.22, 427 aa) folds into the canonical class A 7-TM rhodopsin architecture. ET-1 is a 21-aa bicyclic peptide with two intramolecular disulfide bonds (C1–C15 and C3–C11) that lock its conformation; the C-terminal Trp-Val-Ile-Phe-NH₂ tail is the primary receptor contact motif, inserting deep into the TM2–TM7 orthosteric pocket. A receptor N-terminus/TM7 disulfide (C69–C358) caps the binding cleft and accounts for the near-irreversible binding kinetics of ET-1 (half-life of ET-1/ETA complex measured in hours). Activation drives 6.8 Å outward TM6 displacement, opening the Gs/Gq docking cavity. ETA couples primarily to Gq/11 → PLC → IP3/DAG → Ca²⁺ and PKC, and to G12/13 → RhoA → vasoconstriction and VSMC proliferation. Gi/o and Gs coupling also occur context-dependently. ET-1 has a plasma half-life <5 minutes but acts as an autocrine/paracrine factor - not a circulating hormone. ETB on endothelium clears ~80% of circulating ET-1 via internalization and lysosomal degradation.

Bosentan (dual ETA/ETB antagonist) and ambrisentan/macitentan (ETA-selective) are approved for PAH, improving 6-minute walk distance and delaying clinical worsening. BQ-123 is the canonical ETA-selective peptide research antagonist - a cyclic pentapeptide (cyclo[D-Trp-D-Asp-Pro-D-Val-Leu]) with low-nM affinity and high selectivity. Sarafotoxins (snake venom ET homologs) are research agonist probes. No ET-1 analog is an approved therapeutic. For peptide research, the tractable recipes are: BQ-123 analogs with extended half-lives (N-methylation, lactam bridges) for in vivo studies; C-terminal ET-1 fragments (positions 16–21, the binding pharmacophore) as starting scaffolds for ETA-selective agonist or antagonist design; and ET-1/ET-3 chimeras that selectively shift toward ETB to probe receptor-subtype-specific biology. ETA/ETB heterodimerization alters internalization kinetics and is an underexplored allosteric fork for biased signaling scaffolds.