Research and development of bronchodilators for asthma and COPD with a focus on G protein/K-Ca channel linkage and beta(2)-adrenergic intrinsic efficacy

摘要

Bronchodilators are used to improve symptoms and lung function in asthma and COPD. Airway smooth muscle tone is regulated by both muscarinic and beta(2)-adrenergic receptor activity. Large-conductance Ca2+-activated K+ (K-Ca) channels are activated by beta(2)-adrenergic receptor agonists, via G(s), and suppressed by muscarinic receptor antagonists via G(i). This functional antagonism converges on the G protein/K-Ca channel linkages. Membrane potential regulated by K-Ca channels contributes to airway smooth muscle tension via Ca2+ influx passing through voltage-dependent Ca2+ (VDC) channels. The G(s)/K-Ca/VDC channel linkage is a key process in not only physiological effects, but also in dysfunction of beta(2)-adrenergic receptors and airway remodeling. Moreover, this pathway is involved in the synergistic effects between beta(2)-adrenergic receptor agonists and muscarinic receptor antagonists. Intrinsic efficacy is also an important characteristic for both maintenance and loss of beta(2)-adrenergic action. Allosteric modulators of G protein-coupled receptors contribute not only to this synergistic effect between beta(2)-adrenergic and muscarinic M-2 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 beta(2)-adrenergic desensitization; in contrast exposure to partial agonists does not cause desensitization. Intrinsic efficacy may provide the rationale for the clinical use of beta(2)-adrenergic receptor agonists in asthma and COPD. In conclusion, the G protein/K-Ca linkage and intrinsic efficacy (allosteric effects) may be therapeutic targets for research and development of novel agents against both airway obstruction and airway remodeling. (C) 2015 Elsevier Inc. All rights reserved.