EDNRA

Endothelin Receptor Type A (EDNRA), also known as ET-A or ETAR, is a G protein-coupled receptor predominantly expressed in vascular smooth muscle cells. It binds endothelin-1 (ET-1) with high affinity, activating Gq/11 and Gα12/13 signaling pathways to mediate vasoconstriction, cell proliferation, and fibrosis. EDNRA is central to the endothelin signaling axis, interacting with pathways including PLC-IP3-Ca²⁺, MAPK/ERK, and RhoA/ROCK. Dysregulated EDNRA activity is implicated in pulmonary arterial hypertension (PAH), systemic hypertension, cancer progression (notably prostate and ovarian malignancies), and fibrotic disorders. Pharmacologically, EDNRA antagonists like ambrisentan and macitentan are FDA-approved for PAH, while investigational agents (e.g., zibotentan, clazosentan) target oncology and subarachnoid hemorrhage. Recent trials explore dual EDNRA/EDNRB inhibition to address pathway redundancy in resistant diseases. Structural studies continue to refine subtype-selective antagonist design to minimize off-target effects.