The influences of the M2R-GIRK4-RGS6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart

Kanchan Kulkarni, Xueyi Xie, Ezequiel Marron Fernandez De Velasco, Allison Anderson, Kirill A. Martemyanov, Kevin Wickman, Elena G. Tolkacheva

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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 M2RIKACh 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.

Original languageEnglish (US)
Article numbere0193798
JournalPloS one
Issue number4
StatePublished - Apr 2018

Bibliographical note

Funding Information:
This work was supported by the National Science Foundation grant CAREER PHY-125541 (EGT); National Science Foundation grant DCSD-1662250 (EGT); National Institute of Health grant HL128790 (EGT); National Institute of Health grant HL105550 (KW and KAM) and the National Institute of Health grant HL139090 (AA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would also like to thank Nicholas Carlblom for his assistance with the experiments.

Publisher Copyright:
© 2018 Kulkarni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Dive into the research topics of 'The influences of the M2R-GIRK4-RGS6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart'. Together they form a unique fingerprint.

Cite this