Timo Littmann1, Martin Göttle1, Michael T Reinartz1, Solveig Kälble1, Irving W Wainer1, Takeaki Ozawa1, Roland Seifert2. 1. Institute of Pharmacology, Hannover Medical School, Hannover, Germany (T.L.; M.G.; M.T.R.; S.K., R.S.); Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, Maryland (I.W.W.); and Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan (T.O.). 2. Institute of Pharmacology, Hannover Medical School, Hannover, Germany (T.L.; M.G.; M.T.R.; S.K., R.S.); Laboratory of Clinical Investigation, National Institute on Aging, Baltimore, Maryland (I.W.W.); and Department of Chemistry, School of Science, The University of Tokyo, Tokyo, Japan (T.O.) seifert.roland@mh-hannover.de.
Abstract
UNLABELLED: Beyond canonical signaling via Gαs and cAMP, the concept of functional selectivity at β2-adrenoceptors (β2ARs) describes the ability of adrenergic drugs to stabilize ligand-specific receptor conformations to initiate further signaling cascades comprising additional G-protein classes or β-arrestins (βarr). A set of 65 adrenergic ligands including 40 agonists and 25 antagonists in either racemic or enantiopure forms was used for βarr recruitment experiments based on a split-luciferase assay in a cellular system expressing β2AR. Many agonists showed only (weak) partial agonism regarding βarr recruitment. Potencies and/or efficacies increased depending on the number of chirality centers in (R) configuration; no (S)-configured distomer was more effective at inducing βarr recruitment other than the eutomer. βarr2 was recruited more effectively than βarr1. The analysis of antagonists revealed no significant effects on βarr recruitment. Several agonists showed preference for activation of Gαs GTPase relative to βarr recruitment, and no βarr-biased ligand was identified. IN CONCLUSION: 1) agonists show strong bias for Gαs activation relative to βarr recruitment; 2) agonists recruit βarr1 and βarr2 with subtle differences; and 3) there is no evidence for βarr recruitment by antagonists. U.S. Government work not protected by U.S. copyright.
UNLABELLED: Beyond canonical signaling via Gαs and cAMP, the concept of functional selectivity at β2-adrenoceptors (β2ARs) describes the ability of adrenergic drugs to stabilize ligand-specific receptor conformations to initiate further signaling cascades comprising additional G-protein classes or β-arrestins (βarr). A set of 65 adrenergic ligands including 40 agonists and 25 antagonists in either racemic or enantiopure forms was used for βarr recruitment experiments based on a split-luciferase assay in a cellular system expressing β2AR. Many agonists showed only (weak) partial agonism regarding βarr recruitment. Potencies and/or efficacies increased depending on the number of chirality centers in (R) configuration; no (S)-configured distomer was more effective at inducing βarr recruitment other than the eutomer. βarr2 was recruited more effectively than βarr1. The analysis of antagonists revealed no significant effects on βarr recruitment. Several agonists showed preference for activation of Gαs GTPase relative to βarr recruitment, and no βarr-biased ligand was identified. IN CONCLUSION: 1) agonists show strong bias for Gαs activation relative to βarr recruitment; 2) agonists recruit βarr1 and βarr2 with subtle differences; and 3) there is no evidence for βarr recruitment by antagonists. U.S. Government work not protected by U.S. copyright.
Authors: Alexander R French; Anna M Gutridge; Jinling Yuan; Q Hawk Royer; Richard M van Rijn Journal: Pharmacol Biochem Behav Date: 2022-03-29 Impact factor: 3.697
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