G protein- and β-arrestin Signaling Profiles of Endothelin Derivatives at the Type A Endothelin Receptor. Issue 7 (29th July 2021)

• Record Type: Journal Article
• Authors: Xiong, Xinyu; Nazo, Nour; Revoori, Ritika; Rajagopal, Sudarshan; Sparks, Matthew A.
• Is Part Of: Kidney360. Volume 2:Issue 7(2021)
• Page Start: 1124
• Page End: 1131
• Publication Date: 2021-07-29
• Subjects: nephro-pharmacology -- beta arrestin -- endothelin -- GPCR -- hypertension -- signaling; 616.61
• DOI: 10.34067/KID.0005462020
• Languages: English
• ISSNs: 2641-7650

Abstract

Visual Abstract: Abstract: Key Points: Endothelins activated a wide range of G proteins at the ETA R Endothelin derivatives did display structure-activity relationships in their degrees of agonism β -arrestin 1 and 2 does not augment the diurnal blood pressure, acute, or chronic pressor response to endothelin 1 Background: Endothelin-1 (ET-1) is a potent vasoconstrictor in the cardiovascular system, an effect mediated through the type A endothelin receptor (ETA R), a G protein-coupled receptor (GPCR). Antagonists of the ETA R have shown promising results in randomized clinical trials. However, side effects limit widespread use. Biased agonists have been developed to mitigate the untoward effects of a number of GPCR antagonists. These agents block deleterious G-coupled pathways while stimulating protective β -arrestin pathways. The goal of this study was to test whether there was any significant ligand bias between endothelin derivatives, and whether this could have any physiologic effects in the cardiovascular system. Methods: A panel of endothelin derivatives were tested in assays of G protein signaling and β -arrestin 2 recruitment at the ETA R. We then tested the effects of ET-1 on the vasopressor response in wild-type and β -arrestin 1 and 2 KO mice. Results: We found the endothelins activated a wide range of G proteins at the ETA R, but none of the endothelin derivatives demonstrated significant biased agonism. Endothelin derivatives did display structure-activity relationships with regards to their degrees of agonism. β -arrestin 1 and 2 knockout mice did not display any differences to wild-type mice in the acute pressor response to ET-1, and β -arrestin 2 knockout mice did not display any blood pressure differences to wild-type mice in the chronic responses to ET-1. Conclusions: Our findings are consistent with vasoconstriction being mediated by G proteins with a lack of significant desensitization by β -arrestins at the ETA R. These findings suggest that G protein– and β -arrestin–biased ETA R agonists could have distinct physiologic effects from balanced agonists, although the endothelin peptide scaffold does not appear suitable for designing such ligands.