β-arrestin与β-肾上腺素受体

β-arrestin and β-adrenergic Receptor

2012年度诺贝尔化学奖授予了美国科学家罗伯特.莱夫科维茨(Robert J.Lefkowitz)和布莱恩.克比尔卡(Brian K.Kobilka),以表彰他们在G蛋白偶联受体研究中的贡献。从Robert J.Lefkowitz最初研究β-肾上腺素受体(β-adrenergic receptor,β-AR)减敏机制时发现β-arrestin1至今已有20多年,随着对β-arrestin在细胞信号转导中作用研究的逐渐深入,发现β-arrestin参与β-AR的减敏、内化和降解;近年来又发现,依赖β-arrestin的β-AR信号转导通路具有"偏向激活"现象,并提示这种依赖β-arrestin的"偏向激活"信号转导通路具有心脏保护作用。β-肾上腺素受体阻滞剂的发现和临床应用被视为20世纪药物治疗学上里程碑式的进展,是药物防治心脏疾病的最伟大突破,很多心血管药物都以β-AR为靶点。但是,由于目前受体药物均是针对受体本身的调控,这样在阻断了受体介导的病理性信号通路和功能的同时,也阻断了受体介导的正常生理性信号通路和功能,造成了严重的毒副作用。所以,研发能选择性阻滞β-AR过度激活介导的病理性信号通路和功能的同时,保留受体介导的正常生理性信号通路和功能(如β-arrestin信号通路)的药物,对治疗心血管疾病有重要意义,受体功能选择性的配体药物将成为未来药物的研究方向。该文将回顾β-arrestin的发现过程,综述其与β-AR的相互作用,期望能为心脏疾病的药物治疗提供参考。

The Nobel Prize in Chemistry 2012 was awarded jointly to Robert J. Lefkowitz and Brian K. Kobilka ＂for studies of G-protein-coupled receptors＂. Robert J. Lefkowitz discovered β-arrestinl more than 20 years ago, when he studied the mechanism of [3-AR （β-adrenergic receptor） desensitization, and proved that it in-volves in the desensitization, internalization and degradation of β-AR in his subsequent researches. More recently, new evidence has revealed the ＂biased agonism＂ of β-arrestin dependent signal pathway of β -AR, which is inde-pendent of G protein. Excitingly, this biased signaling was suggested to confer cardioprotection. In addition, β-AR blockers were discovered and widely used in the pharmacotherapy of cardiovascular diseases among many other β-AR targeted cardiovascular drugs, which was a breakthrough in the 20th century. However, most of these drugs take effect only by regulating the β-AR itself and block all of the signal pathways and functions, including both the pathological signaling and effect induced by the increased stimulation of I3-AR and the normal physiological ones, which leads to some severe adverse reactions. Therefore, it will be a great progress in the treatment of cardio- vascular diseases to develop the drug that can both selectively block the harmful signaling and effect and activate the beneficial physiological signaling （such as the β-arrestin signaling） of β-AR. The research and development of ligand drug for β-AR will focus on its highly selective downstream signal pathways. This article is to review the discovery of the β-arrestin and its interaction with β-AR, to offer a reference for the pharmacotherapy of cardiovas-cular diseases.