Antithetic regulation by beta-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airway beta-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 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.
McGraw
Dennis W
DW
University of Cincinnati College of Medicine, 231 Albert Sabin Way, Room G062, Cincinnati, Ohio 45267, USA.
Almoosa
Khalid F
KF
Paul
Richard J
RJ
Kobilka
Brian K
BK
Liggett
Stephen B
SB
D000818:Animals; D015153:Blotting, Western; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D007295:Inositol Phosphates / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000378:metabolism; D054799:Phospholipase C beta; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction; D014132:Trachea / Q000473:pathology; D010738:Type C Phospholipases / Q000378:metabolism*
D016085:Bronchoconstrictor Agents; D007295:Inositol Phosphates; D007527:Isoenzymes; D011943:Receptors, Adrenergic, beta; D010738:Type C Phospholipases; D054799:Phospholipase C beta; C518034:Plcb1 protein, mouse; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins