(a) Mechanism of β-agonist–induced airway smooth muscle relaxation. Ligand binding to the β₂AR activates G_s, leading to adenylyl cyclase (AC) activation, cAMP formation, and subsequent protein kinase A (PKA) activation. PKA phosphorylation of target proteins leads to smooth muscle relaxation and may also inhibit ERK activation. PKA also phosphorylates the β₂AR, leading to increased G_i coupling. In addition, ligand binding causes G protein receptor kinase (GRK) phosphorylation of the β₂AR, recruiting β-arrestin (ARR). (b) Inflammatory events in the asthmatic airway or regular β-agonist use may augment G_i coupling and/or increase β-arrestin binding. Under these circumstances, β-agonists may result in ERK activation, potentially amplifying production of inflammatory cytokines and leading to airway remodeling. Persistent activation of the β₂AR may also lead to phospholipase C-β (PLCβ) expression and consequent airway hyperresponsiveness (8).