TY - JOUR T1 - Recruitment of β-Arrestin 1 and 2 to the β2-Adrenoceptor: Analysis of 65 Ligands JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.115.227959 SP - jpet.115.227959 AU - Timo Littmann AU - Martin Gottle AU - Michael T Reinartz AU - Solveig Kalble AU - Irwing W Wainer AU - Takeaki Ozawa AU - Roland Seifert Y1 - 2015/01/01 UR - http://jpet.aspetjournals.org/content/early/2015/08/25/jpet.115.227959.abstract N2 - Beyond canonical signaling via Gαs and cAMP, the concept of functional selectivity at β2-adrenoceptors (β2AR) 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 64 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 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, (i) agonists show strong bias for Gαs activation relative to βarr recruitment, (ii) agonists recruit βarr1 and βarr2 with subtle differences, and (iii) there is no evidence for βarr recruitment by antagonists. ER -