Asthma is a heterogeneous inflammatory disease of the airways that is associated with airway hyperresponsiveness and airflow limitation. Although asthma was once simply categorized as atopic or nonatopic, emerging analyses over the last few decades have revealed a variety of asthma endotypes that are attributed to numerous pathophysiological mechanisms. The classification of asthma by endotype is primarily routed in different profiles of airway inflammation that contribute to bronchoconstriction. Many asthma therapeutics target G protein-coupled receptors (GPCRs), which either enhance bronchodilation or prevent bronchoconstriction. Short-acting and long-acting β 2-agonists are widely used bronchodilators that signal through the activation of the β 2-adrenergic receptor. Short-acting and long-acting antagonists of muscarinic acetylcholine receptors are used to reduce bronchoconstriction by blocking the action of acetylcholine. Leukotriene antagonists that block the signaling of cysteinyl leukotriene receptor 1 are used as an add-on therapy to reduce bronchoconstriction and inflammation induced by cysteinyl leukotrienes. A number of GPCR-targeting asthma drug candidates are also in different stages of development. Among them, antagonists of prostaglandin D2 receptor 2 have advanced into phase III clinical trials. Others, including antagonists of the adenosine A2B receptor and the histamine H4 receptor, are in early stages of clinical investigation. In the past decade, significant research advancements in pharmacology, cell biology, structural biology, and molecular physiology have greatly deepened our understanding of the therapeutic roles of GPCRs in asthma and drug action on these GPCRs. This review summarizes our current understanding of GPCR signaling and pharmacology in the context of asthma treatment. SIGNIFICANCE STATEMENT: Although current treatment methods for asthma are effective for a majority of asthma patients, there are still a large number of patients with poorly controlled asthma who may experience asthma exacerbations. This review summarizes current asthma treatment methods and our understanding of signaling and pharmacology of G protein-coupled receptors (GPCRs) in asthma therapy, and discusses controversies regarding the use of GPCR drugs and new opportunities in developing GPCR-targeting therapeutics for the treatment of asthma.

中文翻译：

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哮喘治疗中的 G 蛋白偶联受体：药理学和药物作用。


哮喘是一种异质性气道炎症性疾病，与气道高反应性和气流受限相关。尽管哮喘曾经被简单地归类为特应性或非特应性，但过去几十年的新分析揭示了多种哮喘内型，这些内型可归因于多种病理生理机制。哮喘的内型分类主要根据导致支气管收缩的气道炎症的不同情况。许多哮喘治疗药物以 G 蛋白偶联受体 (GPCR) 为靶点，它可以增强支气管扩张或防止支气管收缩。短效和长效 β 2 激动剂是广泛使用的支气管扩张剂，通过激活 β 2 肾上腺素能受体发出信号。毒蕈碱乙酰胆碱受体的短效和长效拮抗剂用于通过阻断乙酰胆碱的作用来减少支气管收缩。阻断半胱氨酰白三烯受体 1 信号传导的白三烯拮抗剂被用作附加疗法，以减少半胱氨酰白三烯引起的支气管收缩和炎症。许多靶向 GPCR 的哮喘候选药物也处于不同的开发阶段。其中前列腺素D2受体2拮抗剂已进入Ⅲ期临床试验。其他药物，包括腺苷 A2B 受体和组胺 H4 受体的拮抗剂，正处于临床研究的早期阶段。在过去的十年中，药理学、细胞生物学、结构生物学和分子生理学方面的重大研究进展极大地加深了我们对 GPCR 在哮喘中的治疗作用以及对这些 GPCR 的药物作用的理解。 这篇综述总结了我们目前对哮喘治疗背景下 GPCR 信号传导和药理学的理解。意义声明：虽然目前的哮喘治疗方法对大多数哮喘患者有效，但仍有大量哮喘控制不佳的患者可能会出现哮喘恶化。本综述总结了当前哮喘治疗方法以及我们对哮喘治疗中G蛋白偶联受体（GPCR）信号传导和药理学的理解，并讨论了GPCR药物使用的争议以及开发GPCR靶向治疗哮喘的新机会。