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M ultiple 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 G_αq-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.