Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America.
Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota, United States of America.
PLoS One. 2018 Apr 18;13(4):e0193798. doi: 10.1371/journal.pone.0193798. eCollection 2018.
A large body of work has established the prominent roles of the atrial M2R-IKACh signaling pathway, and the negative regulatory protein RGS6, in modulating critical aspects of parasympathetic influence on cardiac function, including pace-making, heart rate (HR) variability (HRV), and atrial arrhythmogenesis. Despite increasing evidence of its innervation of the ventricles, and the expression of M2R, IKACh channel subunits, and RGS6 in ventricle, the effects of parasympathetic modulation on ventricular electrophysiology are less clear. The main objective of our study was to investigate the contribution of M2R-IKACh signaling pathway elements in murine ventricular electrophysiology, using in-vivo ECG measurements, isolated whole-heart optical mapping and constitutive knockout mice lacking IKACh (Girk4-/-) or RGS6 (Rgs6-/-). Consistent with previous findings, mice lacking GIRK4 exhibited diminished HR and HRV responses to the cholinergic agonist carbachol (CCh), and resistance to CCh-induced arrhythmic episodes. In line with its role as a negative regulator of atrial M2R-IKACh signaling, loss of RGS6 correlated with a mild resting bradycardia, enhanced HR and HRV responses to CCh, and increased propensity for arrhythmic episodes. Interestingly, ventricles from mice lacking GIRK4 or RGS6 both exhibited increased action potential duration (APD) at baseline, and APD was prolonged by CCh across all genotypes. Similarly, CCh significantly increased the slope of APD restitution in all genotypes. There was no impact of genotype or CCh on either conduction velocity or heterogeneity. Our data suggests that altered parasympathetic signaling through the M2R-IKACh pathway can affect ventricular electrophysiological properties distinct from its influence on atrial physiology.
大量研究已经证实，心房 M2R-IKACh 信号通路和负性调节蛋白 RGS6 在调节副交感神经对心脏功能的关键影响方面发挥着重要作用，包括起搏、心率变异性 (HRV) 和心房心律失常的发生。尽管越来越多的证据表明副交感神经支配心室，并在心室中表达 M2R、IKAch 通道亚基和 RGS6，但副交感神经调节对心室电生理的影响尚不清楚。我们的主要研究目的是使用体内 ECG 测量、离体全心光学映射和缺乏 IKACh（Girk4-/-）或 RGS6（Rgs6-/-）的组成型敲除小鼠，研究 M2R-IKACh 信号通路在小鼠心室电生理中的作用。与先前的发现一致，缺乏 GIRK4 的小鼠表现出对胆碱能激动剂卡巴胆碱（CCh）的心率和 HRV 反应减弱，以及对 CCh 诱导的心律失常发作的抵抗力。与作为心房 M2R-IKACh 信号的负性调节剂的作用一致，RGS6 的缺失与静息性心动过缓轻度相关，对 CCh 的心率和 HRV 反应增强，以及心律失常发作的倾向增加。有趣的是，缺乏 GIRK4 或 RGS6 的心室在基础状态下均表现出动作电位时程 (APD) 延长，而 CCh 使所有基因型的 APD 均延长。同样，CCh 显著增加了所有基因型的 APD restitution 斜率。基因型或 CCh 对传导速度或异质性没有影响。我们的数据表明，通过 M2R-IKACh 途径改变的副交感神经信号可以影响心室电生理特性，与它对心房生理学的影响不同。
