RGS Proteins in Heart: Brakes on the Vagus.
RGS Proteins in Heart: Brakes on the Vagus.
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DOI：
10.3389/fphys.2012.00095
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发表时间：
2012
影响因子：
4
通讯作者：
Fisher RA
中科院分区：
文献类型：
--
作者：
Stewart A;Huang J;Fisher RA
自从Otto Loewi发现迷走神经释放乙酰胆碱（ACh）导致心动过缓和心肌收缩力降低以来，已经过去了近世纪。现在已知心脏的副交感神经控制是由乙酰胆碱刺激G 1/o偶联的毒蕈碱M2受体介导的，其通过Gβγ直接激活G蛋白偶联的内向整流钾（GIRK）通道，导致膜超极化和抑制动作电位（AP）放电。然而，M2 R-GIRK信号传导组分在异源系统中的表达未能重现天然通道门控动力学。随着G蛋白信号转导调节因子（RGS）蛋白的发现，发现了缺失的环节，RGS蛋白作为GTP酶激活蛋白，加速Gα的内在GTP酶活性，导致Gα和Gβγ介导的信号转导终止至下游效应物。在表达RGS不敏感Gαi2突变体（G184 S）的小鼠中进行的研究表明，内源性RGS蛋白是心脏副交感神经信号传导的关键调节因子。最近，两种RGS蛋白已被鉴定为心脏中M2 R信号传导的关键调节剂。RGS 6在心脏中表现出独特的稳健表达，特别是在窦房（SAN）和房室结区域。缺乏RGS 6的小鼠表现出增加的心动过缓和对响应于CCh的SAN AP放电的抑制，以及对ACh诱导的GIRK电流（IKACh）的快速激活和失活动力学和电流脱敏的损失。在缺乏RGS 4的小鼠中观察到类似的发现。因此，RGS蛋白表达或功能的失调可能导致涉及心脏起搏细胞异常电活动的病理。此外，发现RGS 6表达在某些病理条件下在心脏中上调，包括已知在癌症患者中引起危及生命的心脏毒性和心房纤颤的多柔比星治疗。另一方面，增加迷走神经张力可能对心力衰竭具有心脏保护作用，其中乙酰胆碱酯酶抑制剂和迷走神经刺激已被提出作为潜在的治疗方法。总之，这些研究确定了RGS蛋白，特别是RGS 6，作为疾病的新治疗靶点，如病窦综合征或其他涉及心脏自主控制异常的疾病。
It has been nearly a century since Otto Loewi discovered that acetylcholine (ACh) release from the vagus produces bradycardia and reduced cardiac contractility. It is now known that parasympathetic control of the heart is mediated by ACh stimulation of Gi/o-coupled muscarinic M2 receptors, which directly activate G protein-coupled inwardly rectifying potassium (GIRK) channels via Gβγ resulting in membrane hyperpolarization and inhibition of action potential (AP) firing. However, expression of M2R–GIRK signaling components in heterologous systems failed to recapitulate native channel gating kinetics. The missing link was identified with the discovery of regulator of G protein signaling (RGS) proteins, which act as GTPase-activating proteins to accelerate the intrinsic GTPase activity of Gα resulting in termination of Gα- and Gβγ-mediated signaling to downstream effectors. Studies in mice expressing an RGS-insensitive Gαi2 mutant (G184S) implicated endogenous RGS proteins as key regulators of parasympathetic signaling in heart. Recently, two RGS proteins have been identified as critical regulators of M2R signaling in heart. RGS6 exhibits a uniquely robust expression in heart, especially in sinoatrial (SAN) and atrioventricular nodal regions. Mice lacking RGS6 exhibit increased bradycardia and inhibition of SAN AP firing in response to CCh as well as a loss of rapid activation and deactivation kinetics and current desensitization for ACh-induced GIRK current (IKACh). Similar findings were observed in mice lacking RGS4. Thus, dysregulation in RGS protein expression or function may contribute to pathologies involving aberrant electrical activity in cardiac pacemaker cells. Moreover, RGS6 expression was found to be up-regulated in heart under certain pathological conditions, including doxorubicin treatment, which is known to cause life-threatening cardiotoxicity and atrial fibrillation in cancer patients. On the other hand, increased vagal tone may be cardioprotective in heart failure where acetylcholinesterase inhibitors and vagal stimulation have been proposed as potential therapeutics. Together, these studies identify RGS proteins, especially RGS6, as new therapeutic targets for diseases such as sick sinus syndrome or other maladies involving abnormal autonomic control of the heart.
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影响因子：
3.7
作者：
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通讯作者：
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发表时间：
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期刊：
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