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 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.