title: Crosstalk between Gi and Gq/Gs pathways in airway smooth muscle regulates bronchial contractility and relaxation.
abstract: 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.
authors.affiliation: Pulmonary Division, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: McGraw
authors.forename: Jean M
authors.initials: JM
authors.lastname: Elwing
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Fogel
authors.forename: Wayne C H
authors.initials: WC
authors.lastname: Wang
authors.forename: Clare B
authors.initials: CB
authors.lastname: Glinka
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Mihlbachler
authors.forename: Marc E
authors.initials: ME
authors.lastname: Rothenberg
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001986:Bronchial Spasm / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009126:Muscle Relaxation / Q000235:genetics / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D011817:Rabbits; D020239:Receptor Cross-Talk / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019205:GTP-Binding Protein alpha Subunits, Gs