Beta-arrestin-mediated signaling in the heart.
Beta-arrestin-mediated signaling in the heart.
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DOI：
10.1253/circj.cj-08-0734
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发表时间：
2008-11
影响因子：
3.3
通讯作者：
Rockman, Howard A.
中科院分区：
文献类型：
--
作者：
Patel, Priyesh A.;Tilley, Douglas G.;Rockman, Howard A.
关键词：
β-抑制蛋白是一种多功能的衔接蛋白，其在G蛋白偶联受体（GPCR）脱敏中的作用众所周知。令人兴奋的新证据表明，β-arrestin也是一种信号分子，能够在GPCR上启动其自身的G蛋白非依赖性信号传导。研究最多的β-抑制蛋白信号通路之一是涉及促分裂原活化蛋白激酶级联（细胞外调节激酶（ERK））的β-抑制蛋白依赖性活化的通路。ERK信号传导通常通过表皮生长因子受体（EGFR）的激动剂刺激激活，可以通过许多GPCR以β-抑制蛋白依赖性方式激活。最近在心力衰竭动物模型中的研究表明，β-1-肾上腺素能受体（可能还有血管紧张素II 1A型受体）对EGFR/ERK信号传导的β-抑制蛋白依赖性激活具有心脏保护作用。因此，出现了心脏GPCR处的信号传导的新模型，其暗示经典G蛋白介导的信号传导促进心力衰竭中的有害重构，同时将β-抑制蛋白依赖性、G蛋白非依赖性信号传导与心脏保护作用联系起来。基于这一范式，可以鉴定出一类新的药物，称为“偏向配体”，其同时阻断有害的G蛋白信号传导，同时还促进心脏保护性β-arrestin依赖性信号传导，从而导致慢性心脏病治疗的潜在突破。
Beta-arrestin is a multifunctional adapter protein well known for its role in G-protein-coupled receptor (GPCR) desensitization. Exciting new evidence indicates that β-arrestin is also a signaling molecule capable of initiating its own G-protein-independent signaling at GPCRs. One of the best-studied β-arrestin signaling pathways is the one involving β-arrestin-dependent activation of a mitogen-activated protein kinase cascade, the extracellular regulated kinase (ERK). ERK signaling, which is classically activated by agonist stimulation of the epidermal growth factor receptor (EGFR), can be activated by a number of GPCRs in a β-arrestin-dependent manner. Recent work in animal models of heart failure suggests that β-arrestin-dependent activation of EGFR/ERK signaling by the β-1-adrenergic receptor, and possibly the angiotensin II Type 1A receptor, are cardioprotective. Hence, a new model of signaling at cardiac GPCRs has emerged and implicates classical G-protein-mediated signaling with promoting harmful remodeling in heart failure, while concurrently linking β-arrestin-dependent, G-protein-independent signaling with cardioprotective effects. Based on this paradigm, a new class of drugs could be identified, termed “biased ligands”, which simultaneously block harmful G-protein signaling, while also promoting cardioprotective β-arrestin-dependent signaling, leading to a potential breakthrough in the treatment of chronic cardiac disease.
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DOI：
10.1073/pnas.0607583103
发表时间：
2006-10-31
影响因子：
11.1
作者：
Rajagopal, Keshava;Whalen, Erin J.;Lefkowitz, Robert J.
通讯作者：
Lefkowitz, Robert J.
影响因子：
4.8
作者：
Charest, Pascale G.;Oligny-Longpre, Genevieve;Bouvier, Michel
通讯作者：
Bouvier, Michel
影响因子：
56.9
作者：
Nelson, Christopher D.;Perry, Stephen J.;Lefkowitz, Robert J.
通讯作者：
Lefkowitz, Robert J.
影响因子：
8
作者：
Luciano, F;Jacquel, A;Auberger, P
通讯作者：
Auberger, P
影响因子：
4.8
作者：
Ahn, SK;Shenoy, SK;Lefkowitz, RJ
通讯作者：
Lefkowitz, RJ