title: Research and development of bronchodilators for asthma and COPD with a focus on G protein/KCa channel linkage and β2-adrenergic intrinsic efficacy.
abstract: Bronchodilators are used to improve symptoms and lung function in asthma and COPD. Airway smooth muscle tone is regulated by both muscarinic and β2-adrenergic receptor activity. Large-conductance Ca(2+)-activated K(+) (KCa) channels are activated by β2-adrenergic receptor agonists, via Gs, and suppressed by muscarinic receptor antagonists via Gi. This functional antagonism converges on the G protein/KCa channel linkages. Membrane potential regulated by KCa channels contributes to airway smooth muscle tension via Ca(2+) influx passing through voltage-dependent Ca(2+) (VDC) channels. The Gs/KCa/VDC channel linkage is a key process in not only physiological effects, but also in dysfunction of β2-adrenergic receptors and airway remodeling. Moreover, this pathway is involved in the synergistic effects between β2-adrenergic receptor agonists and muscarinic receptor antagonists. Intrinsic efficacy is also an important characteristic for both maintenance and loss of β2-adrenergic action. Allosteric modulators of G protein-coupled receptors contribute not only to this synergistic effect between β2-adrenergic and muscarinic M2 receptors, but also to intrinsic efficacy. The effects of weak partial agonists are suppressed by lowering receptor number, disordering receptor function, and enhancing functional antagonism; in contrast, those of full or strong partial agonists are not suppressed. Excessive exposure to full agonists causes β2-adrenergic desensitization; in contrast, exposure to partial agonists does not cause desensitization. Intrinsic efficacy may provide the rationale for the clinical use of β2-adrenergic receptor agonists in asthma and COPD. In conclusion, the G protein/KCa linkage and intrinsic efficacy (allosteric effects) may be therapeutic targets for research and development of novel agents against both airway obstruction and airway remodeling.
authors.affiliation: Department of Respiratory Medicine and Allergology, Kinki University Faculty of Medicine, Japan. Electronic address: hkume@med.kindai.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kume
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Fukunaga
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Oguma
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy*; D001993:Bronchodilator Agents / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*
chemical_list: D000319:Adrenergic beta-Antagonists; D001993:Bronchodilator Agents; D015220:Calcium Channels; D018727:Muscarinic Antagonists; D024681:Potassium Channels, Calcium-Activated; D019204:GTP-Binding Proteins
keywords: Airway smooth muscle; Allosteric modulators of G protein-coupled receptors; Ca(2+)-activated K(+) channels; Muscarinic receptor antagonists; Voltage-dependent Ca(2+) channels; β(2)-adrenergic receptor agonists