Molecular and Cellular Pharmacology, Vol 1, No 5 (2009)

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Endothelin-1, an Endogenous Irreversible Agonist in Search of an Allosteric Inhibitor

Jo G.R. De Mey, Matthijs G. Compeer, Merlijn J. Meens


Endothelin-1 (ET-1), a 21 amino acid paracrine mediator and long-acting stimulus of G-protein coupled receptors (GPCRs), is implicated in cardiovascular diseases and cancers. We have recently demonstrated that the sensory-motor neurotransmitter calcitonin-gene related peptide (CGRP) selectively inhibits vasoconstrictor responses to ET-1. Here we discuss this and earlier observations in relation to recent insights in GPCR function. We propose that ET-1 acts as an endogenous biased bitopic agonist that binds dynamically and quasi-irreversibly to topographically distinct sites on ETA-receptors. We suggest that allosteric inhibitors of the agonist-binding or of the activation of the secondary quasi-irreversible site might be better suited for the treatment of ET-1-related diseases than inhibitors of endothelin-converting enzyme and competitive ET-receptor antagonists.

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