Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.
Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.
Cells. 2024 Oct 10;13(20):1674. doi: 10.3390/cells13201674.
The prolonged overstimulation of β-adrenergic receptors (β-ARs), a member of the G protein-coupled receptor (GPCR) family, causes abnormalities in the density and functionality of the receptor and contributes to cardiac dysfunctions, leading to the development and progression of heart diseases, especially heart failure (HF). Despite recent advancements in HF therapy, mortality and morbidity rates continue to be high. Treatment with β-AR antagonists (β-blockers) has improved clinical outcomes and reduced overall hospitalization and mortality rates. However, several barriers in the management of HF remain, providing opportunities to develop new strategies that focus on the functions and signal transduction of β-ARs involved in the pathogenesis of HF. As β-AR can signal through multiple pathways influenced by different receptor subtypes, expression levels, and signaling components such as G proteins, G protein-coupled receptor kinases (GRKs), β-arrestins, and downstream effectors, it presents a complex mechanism that could be targeted in HF management. In this narrative review, we focus on the regulation of β-ARs at the receptor, G protein, and effector loci, as well as their signal transductions in the physiology and pathophysiology of the heart. The discovery of potential ligands for β-AR that activate cardioprotective pathways while limiting off-target signaling is promising for the treatment of HF. However, applying findings from preclinical animal models to human patients faces several challenges, including species differences, the genetic variability of β-ARs, and the complexity and heterogeneity of humans. In this review, we also summarize recent updates and future research on the regulation of β-ARs in the molecular basis of HF and highlight potential therapeutic strategies for HF.
β-肾上腺素能受体（β-AR）是 G 蛋白偶联受体（GPCR）家族的成员，其过度持续刺激会导致受体密度和功能异常，并导致心脏功能障碍，进而引发和促进心脏病的发展，尤其是心力衰竭（HF）。尽管 HF 治疗最近取得了进展，但死亡率和发病率仍居高不下。β-AR 拮抗剂（β 受体阻滞剂）的治疗改善了临床结局，并降低了总住院率和死亡率。然而，HF 管理中仍存在一些障碍，为开发新策略提供了机会，这些策略侧重于 HF 发病机制中涉及的β-AR 的功能和信号转导。由于β-AR 可以通过不同受体亚型、表达水平和信号转导成分（如 G 蛋白、G 蛋白偶联受体激酶（GRK）、β-arrestin 和下游效应物）影响的多种途径发出信号，因此呈现出一种复杂的机制，这可能成为 HF 管理的目标。在本综述中，我们重点关注β-AR 在受体、G 蛋白和效应子位置的调节及其在心脏生理和病理生理学中的信号转导。发现激活心脏保护途径而限制非靶点信号的潜在β-AR 配体有望用于 HF 的治疗。然而，将临床前动物模型的研究结果应用于人类患者面临着一些挑战，包括物种差异、β-AR 的遗传变异性以及人类的复杂性和异质性。在本综述中，我们还总结了最近在 HF 分子基础中β-AR 调节的更新和未来研究，并强调了 HF 的潜在治疗策略。
