Role for β-arrestin in mediating paradoxical β2AR and PAR2 signaling in asthma

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 beta-arrestin-dependent, signaling pathways. In human and murine models of asthma, agonist-activation of beta(2)-adrenergic receptor (beta(2)AR) or Protease-activated-receptor-2 (PAR(2)) 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 beta(2)AR and PAR(2) 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 beta-arrestin-dependent signaling promotes inflammation. This review explores the evidence supporting the hypothesis that beta-arrestin-dependent signaling downstream of beta(2)AR and PAR(2) is detrimental in asthma and examines the therapeutic opportunities for selectively targeting this pathway.