title: beta-arrestin-biased agonism at the beta2-adrenergic receptor.
abstract: Classically, the beta 2-adrenergic receptor (beta 2AR) and other members of the seven-transmembrane receptor (7TMR) superfamily activate G protein-dependent signaling pathways in response to ligand stimulus. It has recently been discovered, however, that a number of 7TMRs, including beta 2AR, can signal via beta-arrestin-dependent pathways independent of G protein activation. It is currently unclear if among beta 2AR agonists there exist ligands that disproportionately signal via G proteins or beta-arrestins and are hence "biased." Using a variety of approaches that include highly sensitive fluorescence resonance energy transfer-based methodologies, including a novel assay for receptor internalization, we show that the majority of known beta 2AR agonists exhibit relative efficacies for beta-arrestin-associated activities (beta-arrestin membrane translocation and beta 2AR internalization) identical to the irrelative efficacies for G protein-dependent signaling (cyclic AMP generation). However, for three betaAR ligands there is a marked bias toward beta-arrestin signaling; these ligands stimulate beta-arrestin-dependent receptor activities to a much greater extent than would be expected given their efficacy for G protein-dependent activity. Structural comparison of these biased ligands reveals that all three are catecholamines containing an ethyl substitution on the alpha-carbon, a motif absent on all of the other, unbiased ligands tested. Thus, these studies demonstrate the potential for developing a novel class of 7TMR ligands with a distinct bias for beta-arrestin-mediated signaling.
authors: Departments of Medicine, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors: Matthew T
authors: MT
authors: Drake
authors: Jonathan D
authors: JD
authors: Violin
authors: Erin J
authors: EJ
authors: Whalen
authors: James W
authors: JW
authors: Wisler
authors: Sudha K
authors: SK
authors: Shenoy
authors: Robert J
authors: RJ
authors: Lefkowitz
mesh_terms: D000322:Adrenergic Agonists / Q000737:chemistry / Q000494:pharmacology*; D058666:Adrenergic beta-2 Receptor Agonists; D019390:Arrestins / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008024:Ligands; D021381:Protein Transport / Q000187:drug effects; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000071557:beta-Arrestins
chemical_list: D000322:Adrenergic Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D019390:Arrestins; D008024:Ligands; D018343:Receptors, Adrenergic, beta-2; D000071557:beta-Arrestins; D000242:Cyclic AMP; D019204:GTP-Binding Proteins