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Antithetic regulation by β-adrenergic receptors of G(q) receptor signaling via phospholipase C underlies the airway β-agonist paradox

By Dennis W. McGraw, Khalid F. Almoosa, Richard J. Paul, Brian K. Kobilka and Stephen B. Liggett

Abstract

β-adrenergic receptors (βARs) relax airway smooth muscle and bronchodilate, but chronic β-agonist treatment in asthma causes increased sensitivity to airway constriction (hyperreactivity) and is associated with exacerbations. This paradox was explored using mice with ablated βAR genes (βAR(–/–)) and transgenic mice overexpressing airway smooth muscle β(2)AR (β(2)AR-OE) representing two extremes: absence and persistent activity of airway βAR. Unexpectedly, βAR(–/–) mice, lacking these bronchodilating receptors, had markedly decreased bronchoconstrictive responses to methacholine and other G(q)-coupled receptor agonists. In contrast, β(2)AR-OE mice had enhanced constrictive responses. Contraction to permeabilization with β-escin was unaltered by gene ablation or overexpression. Inositol phosphate accumulation by G(q)-coupled M(3)-muscarinic, thromboxane-A(2), and 5-HT(2) receptors was desensitized in airway smooth muscle cells from βAR(–/–) mice and sensitized in cells from β(2)AR-OE mice. Thus, βAR antithetically regulates constrictive signals, affecting bronchomotor tone/reactivity by additional means other than direct dilatation. Studies of signaling elements in these pathways revealed the nodal point of this cross talk as phospholipase C-β1, whose expression was altered by βAR in a direction and magnitude consistent with the physiologic and cellular responses. These results establish a mechanism of the β-agonist paradox and identify a potential asthma modifier gene (phospholipase C-β1), which may also be a therapeutic target in asthma when chronic β-agonists are required

Topics: Article
Publisher: American Society for Clinical Investigation
Year: 2003
DOI identifier: 10.1172/JCI200318193
OAI identifier: oai:pubmedcentral.nih.gov:171392
Provided by: PubMed Central
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