Airway smooth muscle prostaglandin-EP1 receptors directly modulate β2–adrenergic receptors within a unique heterodimeric complex

摘要

Multiple and paradoxical effects of airway smooth muscle (ASM) 7-transmembrane–spanning receptors activated during asthma, or by treatment with bronchodilators such as β2–adrenergic receptor (β2AR) agonists, indicate extensive receptor crosstalk. We examined the signaling of the prostanoid-EP1 receptor, since its endogenous agonist prostaglandin E2 is abundant in the airway, but its functional implications are poorly defined. Activation of EP1 failed to elicit ASM contraction in mouse trachea via this Gαq-coupled receptor. However, EP1 activation markedly reduced the bronchodilatory function of β2AR agonist, but not forskolin, indicating an early pathway interaction. Activation of EP1 reduced β2AR-stimulated cAMP in ASM but did not promote or augment β2AR phosphorylation or alter β2AR trafficking. Bioluminescence resonant energy transfer showed EP1 and β2AR formed heterodimers, which were further modified by EP1 agonist. In cell membrane [³⁵S]GTPγS binding studies, the presence of the EP1 component of the dimer uncoupled β₂AR from G_αs, an effect accentuated by EP₁ agonist activation. Thus alone, EP₁ does not appear to have a significant direct effect on airway tone but acts as a modulator of the β₂AR, altering G_αs coupling via steric interactions imposed by the EP₁:β₂AR heterodimeric signaling complex and ultimately affecting β₂AR-mediated bronchial relaxation. This mechanism may contribute to β-agonist resistance found in asthma.