Crosstalk between Gi and Gq/Gs pathways in airway smooth muscle regulates bronchial contractility and relaxation

Receptor-mediated airway smooth muscle (ASM) contraction via G(alphaq), and relaxation via G(alphas), underlie the bronchospastic features of asthma and its treatment. Asthma models show increased ASM G(alphai) expression, considered the basis for the proasthmatic phenotypes of enhanced bronchial hy...

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Bibliographic Details
Published in:The Journal of clinical investigation 2007-05, Vol.117 (5), p.1391-1398
Main Authors: McGraw, Dennis W, Elwing, Jean M, Fogel, Kevin M, Wang, Wayne C H, Glinka, Clare B, Mihlbachler, Kathryn A, Rothenberg, Marc E, Liggett, Stephen B
Format: Article
Language:English
Subjects:
Animals
Asthma - genetics
Asthma - metabolism
Asthma - physiopathology
Bronchial Hyperreactivity - genetics
Bronchial Hyperreactivity - metabolism
Bronchial Hyperreactivity - physiopathology
Bronchial Spasm - genetics
Bronchial Spasm - metabolism
Bronchial Spasm - physiopathology
Cells, Cultured
Disease Models, Animal
Female
GTP-Binding Protein alpha Subunit, Gi2 - physiology
GTP-Binding Protein alpha Subunits, Gi-Go - physiology
GTP-Binding Protein alpha Subunits, Gq-G11 - physiology
GTP-Binding Protein alpha Subunits, Gs - physiology
Humans
Mice
Mice, Transgenic
Muscle Relaxation - genetics
Muscle Relaxation - physiology
Muscle, Smooth - physiology
Rabbits
Receptor Cross-Talk - physiology
Signal Transduction - genetics
Signal Transduction - physiology
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Summary:Receptor-mediated airway smooth muscle (ASM) contraction via G(alphaq), and relaxation via G(alphas), underlie the bronchospastic features of asthma and its treatment. Asthma models show increased ASM G(alphai) expression, considered the basis for the proasthmatic phenotypes of enhanced bronchial hyperreactivity to contraction mediated by M(3)-muscarinic receptors and diminished relaxation mediated by beta(2)-adrenergic receptors (beta(2)ARs). A causal effect between G(i) expression and phenotype has not been established, nor have mechanisms whereby G(i) modulates G(q)/G(s) signaling. To delineate isolated effects of altered G(i), transgenic mice were generated overexpressing G(alphai2) or a G(alphai2) peptide inhibitor in ASM. Unexpectedly, G(alphai2) overexpression decreased contractility to methacholine, while G(alphai2) inhibition enhanced contraction. These opposite phenotypes resulted from different crosstalk loci within the G(q) signaling network: decreased phospholipase C and increased PKCalpha, respectively. G(alphai2) overexpression decreased beta(2)AR-mediated airway relaxation, while G(alphai2) inhibition increased this response, consistent with physiologically relevant coupling of this receptor to both G(s) and G(i). IL-13 transgenic mice (a model of asthma), which developed increased ASM G(alphai), displayed marked increases in airway hyperresponsiveness when G(alphai) function was inhibited. Increased G(alphai) in asthma is therefore a double-edged sword: a compensatory event mitigating against bronchial hyperreactivity, but a mechanism that evokes beta-agonist resistance. By selective intervention within these multipronged signaling modules, advantageous G(s)/G(q) activities could provide new asthma therapies.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci30489