Antithetic regulation by β-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airway β-agonist paradox

beta- adrenergic receptors (betaARs) relax airway smooth muscle and bronchodilate, but chronic beta-agonist treatment in asthma causes increased sensitivity to airway constriction (hyperreactivity) and is associated with exacerbations. This paradox was explored using mice with ablated betaAR genes (betaAR(-/-)) and transgenic mice overexpressing airway smooth muscle betaAR (beta(2)AR-OE) representing two extremes: absence and persistent activity of airway betaAR. Unexpectedly, betaAR(-/-) mice, lacking these bronchodilating receptors, had markedly decreased bronchoconstrictive responses to methacholine and other G(q)-coupled receptor agonists. In contrast, beta(2)AR-OE mice had enhanced constrictive responses. Contraction to permeabilization with beta-escin was unaltered by gene ablation or overexpression. Inositol phosphate accumulation by Gq-coupled M-3-muscarinic, thromboxane-A(2), and 5-HT2 receptors was desensitized in airway smooth muscle cells from betaAR(-/-) mice and sensitized in cells from beta(2)AR-OE mice. Thus, betaAR 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-beta1, whose expression was altered by betaAR in a direction and magnitude consistent with the physiologic and cellular responses. These results establish a mechanism of the beta-agonist paradox and identify a potential asthma modifier gene (phospholipase C-betal), which may also be a therapeutic target in asthma when chronic beta-agonists are required.