Airway smooth muscle prostaglandin-EP1 receptors directly modulate [beta]2-adrenergic receptors within a unique heterodimeric complex.
McGraw, Dennis W. 1; Mihlbachler, Kathryn A. 2; Schwarb, Mary Rose 2; Rahman, Fahema F. 1; Small, Kersten M. 1; Almoosa, Khalid F. 1; Liggett, Stephen B. 2
[Article] Journal of Clinical Investigation. 116(5):1400-1409, May 2006.

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Multiple and paradoxical effects of airway smooth muscle (ASM) 7-transmembrane-spanning receptors activated during asthma, or by treatment with bronchodilators such as [beta]2-adrenergic receptor ([beta]2AR) 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 G[alpha]q-coupled receptor. However, EP1 activation markedly reduced the bronchodilatory function of [beta]2AR agonist, but not forskolin, indicating an early pathway interaction. Activation of EP1 reduced [beta]2AR-stimulated cAMP in ASM but did not promote or augment [beta]2AR phosphorylation or alter [beta]2AR trafficking. Bioluminescence resonant energy transfer showed EP1 and [beta]2AR formed heterodimers, which were further modified by EP1 agonist. In cell membrane [35S]GTP[gamma]S binding studies, the presence of the EP1 component of the dimer uncoupled [beta]2AR from G[alpha]s, 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 [beta]2AR, altering G[alpha]s coupling via steric interactions imposed by the EP1:[beta]2AR heterodimeric signaling complex and ultimately affecting [beta]2AR-mediated bronchial relaxation. This mechanism may contribute to [beta]-agonist resistance found in asthma.

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