ArticleAmerican journal of respiratory cell and molecular biology2016
Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction.
Article in American journal of respiratory cell and molecular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 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
17 citing papers in PubMed, 24 citations in OpenAlex.
- Ovarian Cancer G protein-coupled receptor-1 signaling bias dictates anti-contractile effect of benzodiazepines on airway smooth muscle.Respiratory research · 2025Article
- A novel functional role for the classic CNS neurotransmitters, GABA, glycine, and glutamate, in the kidney: potent and opposing regulators of the renal vasculature.American journal of physiology. Renal physiology · 2023Article
- Imidazobenzodiazepine PI320 Relaxes Mouse Peripheral Airways by Inhibiting Calcium Mobilization.American journal of respiratory cell and molecular biology · 2022Article
- Anxiolytics for Bronchodilation: Refinements to GABAAmerican journal of respiratory cell and molecular biology · 2022Article
- β subunits of GABACommunications biology · 2022Article
- GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAPharmacology & therapeutics · 2022Review
- Nebulized MIDD0301 Reduces Airway Hyperresponsiveness in Moderate and Severe Murine Asthma Models.ACS pharmacology & translational science · 2020Article
- Novel Expression of GABAA Receptors on Resistance Arteries That Modulate Myogenic Tone.Journal of vascular research · 2020Article
- Argon reduces the pulmonary vascular tone in rats and humans by GABA-receptor activation.Scientific reports · 2019Article
- A novel GABAAmerican journal of physiology. Lung cellular and molecular physiology · 2019Article
- Obesity-Associated Metabolic Signatures Correlate to Clinical and Inflammatory Profiles of Asthma: A Pilot Study.Allergy, asthma & immunology research · 2018Article
- GABAAmerican journal of physiology. Lung cellular and molecular physiology · 2017Article
- Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABAMolecular pharmaceutics · 2017Article
- Optimization of substituted imidazobenzodiazepines as novel asthma treatments.European journal of medicinal chemistry · 2017Article
- Emerging concepts in smooth muscle contributions to airway structure and function: implications for health and disease.American journal of physiology. Lung cellular and molecular physiology · 2016Review
- Bronchoprotection and bronchorelaxation in asthma: New targets, and new ways to target the old ones.Pharmacology & therapeutics · 2016Review
- Development of GABAA Receptor Subtype-Selective Imidazobenzodiazepines as Novel Asthma Treatments.Molecular pharmaceutics · 2016Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
We previously demonstrated that airway smooth muscle (ASM) cells express γ-aminobutyric acid A receptors (GABA(A)Rs), and that GABA(A)R agonists acutely relax ASM. Among the GABA(A)R α subunits, human ASM cells express only α4 and α5, providing the opportunity for selective pharmacologic targeting. Novel GABA(A)R-positive allosteric modulators designed for enhanced α4/α6 subunit selectivity were synthesized using iterative computational analyses (CMD-45 and XHe-III-74). Studies using oocyte heterologous expression systems confirmed that CMD-45 and XHe-III-74 led to significantly greater augmentation of currents induced by a 3% maximal effective concentration (EC3) of GABA [EC3]-induced currents in oocytes expressing α4 or α6 subunits (along with β3 and γ2) compared with other α subunits. CMD-45 and XHe-III-74 also led to greater ex vivo relaxation of contracted wild-type mouse tracheal rings compared with tracheal rings from GABA(A)R α4 subunit (Gabra4) knockout mice. Furthermore, CMD-45 and XHe-III-74 significantly relaxed precontracted human ASM ex vivo, and, at a low concentration, both ligands led to a significant leftward shift in albuterol-mediated ASM relaxation. In vivo, inhaled XHe-III-74 reduced respiratory system resistance in an asthmatic mouse model. Pretreatment of human ASM cells with CMD-45 and XHe-III-74 inhibited histamine-induced increases in intracellular calcium concentrations in vitro, an effect that was lost when calcium was omitted from the extracellular buffer, suggesting that inhibition of calcium influx due to alterations in plasma membrane potential may play a role in the mechanism of ASM relaxation. Selective targeting of the GABA(A)R α4 subunit with inhaled ligands may be a novel therapeutic pathway to treat bronchoconstriction, while avoiding sedative central nervous system effects, which are largely mediated by α1-3 subunit-containing GABA(A)Rs in the brain.
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