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Airway smooth muscle prostaglandin-EP1 receptors directly modulate β2–adrenergic receptors within a unique heterodimeric complex
Dennis W. McGraw, … , Khalid F. Almoosa, Stephen B. Liggett
Dennis W. McGraw, … , Khalid F. Almoosa, Stephen B. Liggett
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1400-1409. https://doi.org/10.1172/JCI25840.
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Research Article Inflammation

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

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Abstract

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 Gαs, 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 Gαs 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.

Authors

Dennis W. McGraw, Kathryn A. Mihlbachler, Mary Rose Schwarb, Fahema F. Rahman, Kersten M. Small, Khalid F. Almoosa, Stephen B. Liggett

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Figure 1

EP1 receptor expression and signal transduction in murine ASM cells.

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                  EP1
                  receptor expression and signal ...
(A) EP1 gene expression was detected in cultured murine ASM cells by RT-PCR. The 501-bp product (left) corresponding to sequence from the EP1 receptor open reading frame was only detected in reactions that included reverse transcriptase (+RT) and hybridized by Southern blots to an EP1-specific probe (right). (B) The EP1-selective agonist 17-PTP (1 μM) stimulated inositol phosphate (IP) production in murine ASM ~70% above basal levels (n = 4). Thrombin-stimulated inositol phosphate production was used for a positive control. *P < 0.05 versus basal. (C) Both 17-PTP and acetylcholine-stimulated [Ca2+]i transients in ASM cells. Shown is a representative experiment using the doses shown in D. (D) Maximal agonist-stimulated [Ca2+]i transients in ASM cells exposed to the indicated doses of agonists. Data are mean ± SEM of 5 experiments. Cch, carbachol; RFU, relative fluorescence units.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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