Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Circ Res. 2010 Nov 26;107(11):1345-9. doi: 10.1161/CIRCRESAHA.110.224220. Epub 2010 Sep 23.
Parasympathetic regulation of heart rate is mediated by acetylcholine binding to G protein-coupled muscarinic M2 receptors, which activate heterotrimeric G(i/o) proteins to promote G protein-coupled inwardly rectifying K(+) (GIRK) channel activation. Regulator of G protein signaling (RGS) proteins, which function to inactivate G proteins, are indispensable for normal parasympathetic control of the heart. However, it is unclear which of the more than 20 known RGS proteins function to negatively regulate and thereby ensure normal parasympathetic control of the heart.
To examine the specific contribution of RGS6 as an essential regulator of parasympathetic signaling in heart.
We developed RGS6 knockout mice to determine the functional impact of loss of RGS6 on parasympathetic regulation of cardiac automaticity. RGS6 exhibited a uniquely robust expression in the heart, particularly in sinoatrial and atrioventricular nodal regions. Loss of RGS6 provoked dramatically exaggerated bradycardia in response to carbachol in mice and isolated perfused hearts and significantly enhanced the effect of carbachol on inhibition of spontaneous action potential firing in sinoatrial node cells. Consistent with a role of RGS6 in G protein inactivation, RGS6-deficient atrial myocytes exhibited a significant reduction in the time course of acetylcholine-activated potassium current (I(K)(ACh)) activation and deactivation, as well as the extent of I(K)(ACh) desensitization.
RGS6 is a previously unrecognized, but essential, regulator of parasympathetic activation in heart, functioning to prevent parasympathetic override and severe bradycardia. These effects likely result from actions of RGS6 as a negative regulator of G protein activation of GIRK channels.
心率的副交感神经调节是通过乙酰胆碱与 G 蛋白偶联毒蕈碱 M2 受体结合介导的，该受体激活异三聚体 G(i/o)蛋白，促进 G 蛋白偶联内向整流钾 (GIRK) 通道激活。G 蛋白信号转导调节因子（RGS）蛋白是 G 蛋白失活所必需的，对于正常的副交感神经对心脏的控制是不可或缺的。然而，目前尚不清楚 20 多种已知的 RGS 蛋白中的哪一种起负调控作用，从而确保正常的副交感神经对心脏的控制。
研究 RGS6 作为心脏副交感信号负调控的必需调节因子的具体作用。
我们构建了 RGS6 敲除小鼠，以确定 RGS6 缺失对心脏自主神经副交感调节的功能影响。RGS6 在心脏中表现出独特的强表达，特别是在窦房结和房室结区域。RGS6 缺失导致小鼠和离体灌流心脏对卡巴胆碱的反应性显著加剧心动过缓，并显著增强了卡巴胆碱对窦房结细胞自发动作电位放电的抑制作用。与 RGS6 在 G 蛋白失活中的作用一致，RGS6 缺陷性心房肌细胞表现出乙酰胆碱激活钾电流（I(K)(ACh)）激活和失活的时间过程以及 I(K)(ACh)脱敏的程度显著降低。
RGS6 是心脏副交感神经激活的一个以前未被识别的但必需的调节因子，其作用是防止副交感神经的抑制作用和严重心动过缓。这些效应可能是由于 RGS6 作为 GIRK 通道的 G 蛋白激活的负调节剂的作用所致。
