G protein- and β-arrestin Signaling Profiles of Endothelin Derivatives at the Type A Endothelin Receptor
| Autor: | Ritika Revoori, Matthew A. Sparks, Xinyu Xiong, Sudarshan Rajagopal, Nour Nazo |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.hormone Arrestins G protein 030204 cardiovascular system & hematology Pharmacology Endothelins Mice 03 medical and health sciences 0302 clinical medicine GTP-Binding Proteins Arrestin Functional selectivity Animals Medicine Receptor beta-Arrestins G protein-coupled receptor Original investigation Endothelin-1 business.industry General Medicine Receptor Endothelin A beta-Arrestin 1 030104 developmental biology Knockout mouse business Endothelin receptor |
| Zdroj: | Kidney360 |
| Popis: | Background Endothelin-1 (ET-1) is a potent vasoconstrictor in the cardiovascular system, an effect mediated through the type A endothelin receptor (ETAR), a G protein-coupled receptor (GPCR). Antagonists of the ETAR 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 ETAR. 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 ETAR, 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 ETAR. These findings suggest that G protein– and β-arrestin–biased ETAR agonists could have distinct physiologic effects from balanced agonists, although the endothelin peptide scaffold does not appear suitable for designing such ligands. |
| Databáze: | OpenAIRE |
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