title: Role for β-arrestin in mediating paradoxical β2AR and PAR2 signaling in asthma.
abstract: G protein-coupled receptors (GPCRs) utilize (at least) two signal transduction pathways to elicit cellular responses including the classic G protein-dependent, and the more recently discovered β-arrestin-dependent, signaling pathways. In human and murine models of asthma, agonist-activation of β2-adrenergic receptor (β2AR) or Protease-activated-receptor-2 (PAR2) results in relief from bronchospasm via airway smooth muscle relaxation. However, chronic activation of these receptors, leads to pro-inflammatory responses. One plausible explanation underlying the paradoxical effects of β2AR and PAR2 agonism in asthma is that the beneficial and harmful effects are associated with distinct signaling pathways. Specifically, G protein-dependent signaling mediates relaxation of airway smooth muscle, whereas β-arrestin-dependent signaling promotes inflammation. This review explores the evidence supporting the hypothesis that β-arrestin-dependent signaling downstream of β2AR and PAR2 is detrimental in asthma and examines the therapeutic opportunities for selectively targeting this pathway.
authors.affiliation: Duke University School of Nursing, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: walke082@mc.duke.edu.
authors.forename: Julia K L
authors.initials: JK
authors.lastname: Walker
authors.affiliation: Division of Biomedical Sciences, University of California, Riverside, CA 92521, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: DeFea
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D001249:Asthma / Q000378:metabolism*; D006801:Humans; D044464:Receptor, PAR-2 / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D044464:Receptor, PAR-2; D018343:Receptors, Adrenergic, beta-2; D000071557:beta-Arrestins