ArticleThe Journal of clinical investigation2003
Antithetic regulation by beta-adrenergic receptors of Gq receptor signaling via phospholipase C underlies the airway beta-agonist paradox.
Article in The Journal of clinical investigation, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
51 citing papers in PubMed, 128 citations in OpenAlex.
- Regulatory haplotypes in ARG1 are associated with altered bronchodilator response.American journal of respiratory and critical care medicine · 2011Trial
- The safety and effects of the beta-blocker, nadolol, in mild asthma: an open-label pilot study.Pulmonary pharmacology & therapeutics · 2008Trial
- beta-Adrenergic receptor polymorphisms and response to salmeterol.American journal of respiratory and critical care medicine · 2006Trial
- Limited beta2-adrenoceptor haplotypes display different agonist mediated airway responses in asthmatics.Respiratory research · 2006Trial
- Oxylipin Profiling of Airway Structural Cells Is Unique and Modified by Relevant Stimuli.Journal of proteome research · 2025Article
- βScientific reports · 2017Article
- Heat Shock-Related Protein 20 Peptide Decreases Human Airway Constriction Downstream of β2-Adrenergic Receptor.American journal of respiratory cell and molecular biology · 2016Article
- Attenuation of airway smooth muscle contractility via flavonol-mediated inhibition of phospholipase-Cβ.American journal of physiology. Lung cellular and molecular physiology · 2016Article
- Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction.American journal of respiratory cell and molecular biology · 2016Article
- A long-acting β2-adrenergic agonist increases the expression of muscarine cholinergic subtype‑3 receptors by activating the β2-adrenoceptor cyclic adenosine monophosphate signaling pathway in airway smooth muscle cells.Molecular medicine reports · 2015Article
- LAMA/LABA vs ICS/LABA in the treatment of COPD in Japan based on the disease phenotypes.International journal of chronic obstructive pulmonary disease · 2015Review
- The pharmacological rationale for combining muscarinic receptor antagonists and β-adrenoceptor agonists in the treatment of airway and bladder disease.Current opinion in pharmacology · 2014Review
- The effect of deficient muscarinic signaling on commonly reported biochemical effects in schizophrenia and convergence with genetic susceptibility loci in explaining symptom dimensions of psychosis.Frontiers in pharmacology · 2014Article
- The Sophora flavescens flavonoid compound trifolirhizin inhibits acetylcholine induced airway smooth muscle contraction.Phytochemistry · 2013Article
- Bitter taste receptors on airway smooth muscle as targets for novel bronchodilators.Expert opinion on therapeutic targets · 2013Review
- Prenatal and postnatal polycyclic aromatic hydrocarbon exposure, airway hyperreactivity, and Beta-2 adrenergic receptor function in sensitized mouse offspring.Journal of toxicology · 2013Article
- The safety of long-acting β2-agonists in the treatment of stable chronic obstructive pulmonary disease.International journal of chronic obstructive pulmonary disease · 2013Review
- An environmental epigenetic study of ADRB2 5'-UTR methylation and childhood asthma severity.Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology · 2012Article
- TAS2R activation promotes airway smooth muscle relaxation despite β(2)-adrenergic receptor tachyphylaxis.American journal of physiology. Lung cellular and molecular physiology · 2012Article
- Novel cAMP signalling paradigms: therapeutic implications for airway disease.British journal of pharmacology · 2012Review
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.