| First Author | McGraw DW | Year | 2003 |
| Journal | J Clin Invest | Volume | 112 |
| Issue | 4 | Pages | 619-26 |
| PubMed ID | 12925702 | Mgi Jnum | J:85126 |
| Mgi Id | MGI:2672939 | Doi | 10.1172/JCI18193 |
| Citation | McGraw DW, et al. (2003) Antithetic regulation by beta-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airway beta-agonist paradox. J Clin Invest 112(4):619-26 |
| abstractText | 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 beta2AR (beta2AR-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 Gq-coupled receptor agonists. In contrast, beta2AR-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 M3-muscarinic, thromboxane-A2, and 5-HT2 receptors was desensitized in airway smooth muscle cells from betaAR-/- mice and sensitized in cells from beta2AR-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-beta1), which may also be a therapeutic target in asthma when chronic beta-agonists are required. |
