Airway smooth muscle prostaglandin-EP1 receptors directly modulate  2-adrenergic receptors within a unique heterodimeric complex

Multiple and paradoxical effects of airway smooth muscle (ASM) 7-transmembrane-spanning receptors activated during asthma, or by treatment with bronchodilators such as 2 -adrenergic receptor ( 2 AR) agonists, indicate extensive receptor crosstalk. We examined the signaling of the prostanoid-EP 1 receptor, since its endogenous agonist prostaglandin E 2 is abundant in the airway, but its functional implications are poorly defined. Activation of EP 1 failed to elicit ASM contraction in mouse trachea via this G q -coupled receptor. However, EP 1 activation markedly reduced the bronchodilatory function of 2 AR agonist, but not forskolin, indicating an early pathway interaction. Activation of EP 1 reduced 2 AR-stimulated cAMP in ASM but did not promote or augment 2 AR phosphorylation or alter 2 AR trafficking. Bioluminescence resonant energy transfer showed EP 1 and 2 AR formed heterodimers, which were further modified by EP 1 agonist. In cell membrane 35 SGTPS binding studies, the presence of the EP 1 component of the dimer uncoupled 2 AR from G s , an effect accentuated by EP 1 agonist activation. Thus alone, EP 1 does not appear to have a significant direct effect on airway tone but acts as a modulator of the 2 AR, altering G s coupling via steric interactions imposed by the EP 1 : 2 AR heterodimeric signaling complex and ultimately affecting 2 AR-mediated bronchial relaxation. This mechanism may contribute to -agonist resistance found in asthma.