title: Endothelin-1: Biosynthesis, Signaling and Vasoreactivity.
abstract: Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide originally isolated from endothelial cells. Its synthesis, mainly regulated at the gene transcription level, involves processing of a precursor by a furin-type proprotein convertase to an inactive intermediate, big ET-1. The latter peptide can then be cleaved directly by an endothelin-converting enzyme (ECE) into ET-1 or reach the active metabolite through a two-step process involving chymase hydrolyzing big ET-1 to ET-1 (1-31), itself needing conversion to ET-1 by neprilysin (NEP) to exert physiological activity. ET-1 signals through two G protein-coupled receptors, endothelin receptor A (ETA) and endothelin receptor B (ETB). Both receptors induce an increase in intracellular Ca(2+), mainly from the extracellular space through voltage-independent mechanisms, the receptor-operated channels and store-operated channels. ET-1 also induces signaling through epidermal growth factor receptor transactivation, oxidative stress induction, rho-kinase, and the activation (ETA) or inhibition (ETB) of the adenylate cyclase/cyclic adenosine monophosphate pathway. Arterial vasoconstriction is mediated mainly by the ETA receptor. ET-1, via endothelium-located ETB, relaxes arteries or constricts vessels following activation of the same receptor type on the smooth muscle, where it can interact with ETA. In addition, ETB-dependent vasoconstriction seems more prominent in the venous vasculature. A better understanding of how ET-1 is synthesized and how ETA and ETB receptors interact could help design better pharmacological agents in the treatment of cardiovascular diseases where targeting the ET-1 system is indicated.
authors.affiliation: Université de Sherbrooke, Sherbrooke, QC, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Houde
authors.affiliation: Université de Sherbrooke, Sherbrooke, QC, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Desbiens
authors.affiliation: Université de Sherbrooke, Sherbrooke, QC, Canada. Electronic address: pedro.dorleans-juste@usherbrooke.ca.
authors.forename: P
authors.initials: P
authors.lastname: D'Orléans-Juste
mesh_terms: D000818:Animals; D019332:Endothelin-1 / Q000378:metabolism*; D006801:Humans; D044022:Receptor, Endothelin A / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014661:Vasoconstriction
chemical_list: D019332:Endothelin-1; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B
keywords: Endothelin receptors; Endothelin-1; Endothelin-converting enzyme; Endothelium; Signaling; Vascular smooth muscle; Vasoconstriction