title: Recruitment of β-arrestin 1 and 2 to the β2-adrenoceptor: analysis of 65 ligands.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: 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.).
authors: Timo
authors: T
authors: Littmann
authors: 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.).
authors: Martin
authors: M
authors: Göttle
authors: 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.).
authors: Michael T
authors: MT
authors: Reinartz
authors: 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.).
authors: Solveig
authors: S
authors: Kälble
authors: 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.).
authors: Irving W
authors: IW
authors: Wainer
authors: 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.).
authors: Takeaki
authors: T
authors: Ozawa
authors: 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.
authors: Roland
authors: R
authors: Seifert
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D058672:Adrenergic beta-2 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D019390:Arrestins / Q000378:metabolism*; D002395:Catecholamines / Q000378:metabolism; D054333:Drug Partial Agonism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008024:Ligands; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
chemical_list: C000605253:ARRB1 protein, human; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D019390:Arrestins; D002395:Catecholamines; D008024:Ligands; D018343:Receptors, Adrenergic, beta-2; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D019205:GTP-Binding Protein alpha Subunits, Gs; D007545:Isoproterenol