Stewart Adele, Huang Jie, Fisher Rory A
Department of Pharmacology, Carver College of Medicine, University of Iowa Iowa City, IA, USA.
Front Physiol. 2012 Apr 13;3:95. doi: 10.3389/fphys.2012.00095. eCollection 2012.
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 G(i/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 Gα(i2) 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 (I(KACh)). 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.
自奥托·勒维发现迷走神经释放的乙酰胆碱（ACh）会导致心动过缓和心脏收缩力减弱以来，已经过去了近一个世纪。现在已知心脏的副交感神经控制是由ACh刺激G（i/o）偶联的毒蕈碱M2受体介导的，该受体通过Gβγ直接激活G蛋白偶联内向整流钾（GIRK）通道，导致膜超极化并抑制动作电位（AP）发放。然而，异源系统中M2R - GIRK信号成分的表达未能重现天然通道的门控动力学。随着G蛋白信号调节剂（RGS）蛋白的发现，缺失的环节得以确定，RGS蛋白作为GTP酶激活蛋白，加速Gα的内在GTP酶活性，从而终止Gα和Gβγ介导的向下游效应器的信号传导。对表达RGS不敏感的Gα（i2）突变体（G184S）的小鼠的研究表明，内源性RGS蛋白是心脏副交感神经信号的关键调节因子。最近，两种RGS蛋白已被确定为心脏中M2R信号的关键调节因子。RGS6在心脏中表现出独特的高表达，尤其是在窦房结（SAN）和房室结区域。缺乏RGS6的小鼠对CCh的反应表现出心动过缓和窦房结AP发放抑制增加，以及对ACh诱导的GIRK电流（I（KACh））的快速激活和失活动力学及电流脱敏丧失。在缺乏RGS4的小鼠中也观察到了类似的结果。因此，RGS蛋白表达或功能的失调可能导致涉及心脏起搏器细胞异常电活动的病理状况。此外，发现在某些病理条件下，包括多柔比星治疗（已知会在癌症患者中引起危及生命的心脏毒性和心房颤动），心脏中RGS6的表达会上调。另一方面，迷走神经张力增加在心力衰竭中可能具有心脏保护作用，其中乙酰胆碱酯酶抑制剂和迷走神经刺激已被提议作为潜在的治疗方法。总之，这些研究确定RGS蛋白，尤其是RGS6，是诸如病态窦房结综合征或其他涉及心脏自主神经控制异常的疾病的新治疗靶点。
