ArticlePloS one2015
Defective Resensitization in Human Airway Smooth Muscle Cells Evokes β-Adrenergic Receptor Dysfunction in Severe Asthma.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- NO modulates human airway smooth muscle function by altering glucose-6-phosphate dehydrogenase effects on sGC function in asthma.Redox biology · 2026Article
- A-Kinase-Anchoring Protein Subtypes Differentially Regulate GPCR Signaling and Function in Human Airway Smooth Muscle.American journal of respiratory cell and molecular biology · 2025Article
- Update on the Role of β2AR and TRPV1 in Respiratory Diseases.International journal of molecular sciences · 2024Review
- Adrenoceptor Desensitization: Current Understanding of Mechanisms.Pharmacological reviews · 2024Review
- Optical Control of Cell-Surface and Endomembrane-Exclusive β-Adrenergic Receptor Signaling.bioRxiv : the preprint server for biology · 2024Article
- Protein Phosphatase 2A as a Therapeutic Target in Pulmonary Diseases.Medicina (Kaunas, Lithuania) · 2023Review
- S-nitrosylation is required for βMolecular cell · 2022Article
- Phosphodiesterase 4 mediates interleukin-8-induced heterologous desensitization of the βFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Identification and Characterization of Novel Bronchodilator Agonists Acting at Human Airway Smooth Muscle Cell TAS2R5.ACS pharmacology & translational science · 2020Article
- Reduced suppressive effect of βRespiratory research · 2017Article
- Phosphoinositide 3-Kinase in Asthma: Novel Roles and Therapeutic Approaches.American journal of respiratory cell and molecular biology · 2017Review
- Inhibition of PI3K promotes dilation of human small airways in a rho kinase-dependent manner.British journal of pharmacology · 2016Article
- Cardiac β2-Adrenergic Receptor Phosphorylation at Ser355/356 Regulates Receptor Internalization and Functional Resensitization.PloS one · 2016Article
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
β2-adrenergic receptor (β2AR) agonists (β2-agonist) are the most commonly used therapy for acute relief in asthma, but chronic use of these bronchodilators paradoxically exacerbates airway hyper-responsiveness. Activation of βARs by β-agonist leads to desensitization (inactivation) by phosphorylation through G-protein coupled receptor kinases (GRKs) which mediate β-arrestin binding and βAR internalization. Resensitization occurs by dephosphorylation of the endosomal βARs which recycle back to the plasma membrane as agonist-ready receptors. To determine whether the loss in β-agonist response in asthma is due to altered βAR desensitization and/or resensitization, we used primary human airway smooth muscle cells (HASMCs) isolated from the lungs of non-asthmatic and fatal-asthmatic subjects. Asthmatic HASMCs have diminished adenylyl cyclase activity and cAMP response to β-agonist as compared to non-asthmatic HASMCs. Confocal microscopy showed significant accumulation of phosphorylated β2ARs in asthmatic HASMCs. Systematic analysis of desensitization components including GRKs and β-arrestin showed no appreciable differences between asthmatic and non-asthmatic HASMCs. However, asthmatic HASMC showed significant increase in PI3Kγ activity and was associated with reduction in PP2A activity. Since reduction in PP2A activity could alter receptor resensitization, endosomal fractions were isolated to assess the agonist ready β2ARs as a measure of resensitization. Despite significant accumulation of β2ARs in the endosomes of asthmatic HASMCs, endosomal β2ARs cannot robustly activate adenylyl cyclase. Furthermore, endosomes from asthmatic HASMCs are associated with significant increase in PI3Kγ and reduced PP2A activity that inhibits β2AR resensitization. Our study shows that resensitization, a process considered to be a homeostasis maintaining passive process is inhibited in asthmatic HASMCs contributing to β2AR dysfunction which may underlie asthma pathophysiology and loss in asthma control.
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