Airway smooth muscle prostaglandin-EP1 receptors directly modulate beta2-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 beta(2)-adrenergic receptor (beta(2)AR) agonists, indicate extensive receptor crosstalk. We examined the signaling of the prostanoid...

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Bibliographic Details
Published in:The Journal of clinical investigation 2006-05, Vol.116 (5), p.1400-1409
Main Authors: McGraw, Dennis W, Mihlbachler, Kathryn A, Schwarb, Mary Rose, Rahman, Fahema F, Small, Kersten M, Almoosa, Khalid F, Liggett, Stephen B
Format: Article
Language:English
Subjects:
Animals
Cell Line
Cercopithecus aethiops
Colforsin - metabolism
COS Cells
Dimerization
Guanosine 5'-O-(3-Thiotriphosphate) - metabolism
Humans
Mice
Muscle, Smooth - metabolism
Receptors, Adrenergic, beta-2 - metabolism
Receptors, Adrenergic, beta-2 - physiology
Receptors, Prostaglandin E - physiology
Receptors, Prostaglandin E, EP1 Subtype
Signal Transduction
Trachea - cytology
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Summary: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(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(alphaq)-coupled receptor. However, EP(1) activation markedly reduced the bronchodilatory function of beta(2)AR agonist, but not forskolin, indicating an early pathway interaction. Activation of EP(1) reduced beta(2)AR-stimulated cAMP in ASM but did not promote or augment beta(2)AR phosphorylation or alter beta(2)AR trafficking. Bioluminescence resonant energy transfer showed EP(1) and beta(2)AR formed heterodimers, which were further modified by EP(1) agonist. In cell membrane [(35)S]GTPgammaS binding studies, the presence of the EP(1) component of the dimer uncoupled beta(2)AR from G(alphas), 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 beta(2)AR, altering G(alphas) coupling via steric interactions imposed by the EP(1):beta(2)AR heterodimeric signaling complex and ultimately affecting beta(2)AR-mediated bronchial relaxation. This mechanism may contribute to beta-agonist resistance found in asthma.
ISSN:0021-9738
1558-8238