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.

Figure 1. Dual signaling pathways and paradoxical response to bronchodilators

Activation of β₂AR or PAR₂ leads to both β-arrestin-dependent and G protein-dependent signaling. Activation of the G protein-dependent pathway leads to bronchorelaxation whereas activation of the β-arrestin-2-dependent signaling pathway is pro-asthmatic. (β₂AR, beta-2-adrenergic receptor; PAR₂, protease-activated-receptor-2; ASM, airway smooth muscle.

Figure 2. Impact of β-arrestin-dependent signaling on drug discovery for asthma treatment

a) Unbiased GPCR ligand functionally activates both the G protein- and Barrestin-dependent signaling pathways leading to bronchorelaxation and inflammation, respectively; b) Biased ligand favors G signaling over β-arrestin signaling; c) Allosteric modulation of the receptor facilitates biased signaling even though the ligand is unbiased; d) Intracellular inhibition of β-arrestin-dependent signaling; e) Low dose unbiased agonist results in normal ASM relaxation due to intracellular inhibition of β-arrestin-mediated constraint of G protein signaling. UBL, unbiased ligand; BL, biased ligand; AM, allosteric modulator; GPCR, G protein-coupled receptor, ASM relax, airway smooth muscle relaxation; Pro-inflam, pro-inflammatory; βarr, β-arrestin.