The influences of the M2R-GIRK4-RGS6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart.
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 arrhythm...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2018-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC5905881?pdf=render |
id |
doaj-6b3d2e0501fb4246bf0b8bc821bacd30 |
---|---|
record_format |
Article |
spelling |
doaj-6b3d2e0501fb4246bf0b8bc821bacd302020-11-25T02:01:09ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01134e019379810.1371/journal.pone.0193798The influences of the M2R-GIRK4-RGS6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart.Kanchan KulkarniXueyi XieEzequiel Marron Fernandez de VelascoAllison AndersonKirill A MartemyanovKevin WickmanElena G TolkachevaA 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.http://europepmc.org/articles/PMC5905881?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kanchan Kulkarni Xueyi Xie Ezequiel Marron Fernandez de Velasco Allison Anderson Kirill A Martemyanov Kevin Wickman Elena G Tolkacheva |
spellingShingle |
Kanchan Kulkarni Xueyi Xie Ezequiel Marron Fernandez de Velasco Allison Anderson Kirill A Martemyanov Kevin Wickman Elena G Tolkacheva The influences of the M2R-GIRK4-RGS6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart. PLoS ONE |
author_facet |
Kanchan Kulkarni Xueyi Xie Ezequiel Marron Fernandez de Velasco Allison Anderson Kirill A Martemyanov Kevin Wickman Elena G Tolkacheva |
author_sort |
Kanchan Kulkarni |
title |
The influences of the M2R-GIRK4-RGS6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart. |
title_short |
The influences of the M2R-GIRK4-RGS6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart. |
title_full |
The influences of the M2R-GIRK4-RGS6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart. |
title_fullStr |
The influences of the M2R-GIRK4-RGS6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart. |
title_full_unstemmed |
The influences of the M2R-GIRK4-RGS6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart. |
title_sort |
influences of the m2r-girk4-rgs6 dependent parasympathetic pathway on electrophysiological properties of the mouse heart. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2018-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC5905881?pdf=render |
work_keys_str_mv |
AT kanchankulkarni theinfluencesofthem2rgirk4rgs6dependentparasympatheticpathwayonelectrophysiologicalpropertiesofthemouseheart AT xueyixie theinfluencesofthem2rgirk4rgs6dependentparasympatheticpathwayonelectrophysiologicalpropertiesofthemouseheart AT ezequielmarronfernandezdevelasco theinfluencesofthem2rgirk4rgs6dependentparasympatheticpathwayonelectrophysiologicalpropertiesofthemouseheart AT allisonanderson theinfluencesofthem2rgirk4rgs6dependentparasympatheticpathwayonelectrophysiologicalpropertiesofthemouseheart AT kirillamartemyanov theinfluencesofthem2rgirk4rgs6dependentparasympatheticpathwayonelectrophysiologicalpropertiesofthemouseheart AT kevinwickman theinfluencesofthem2rgirk4rgs6dependentparasympatheticpathwayonelectrophysiologicalpropertiesofthemouseheart AT elenagtolkacheva theinfluencesofthem2rgirk4rgs6dependentparasympatheticpathwayonelectrophysiologicalpropertiesofthemouseheart AT kanchankulkarni influencesofthem2rgirk4rgs6dependentparasympatheticpathwayonelectrophysiologicalpropertiesofthemouseheart AT xueyixie influencesofthem2rgirk4rgs6dependentparasympatheticpathwayonelectrophysiologicalpropertiesofthemouseheart AT ezequielmarronfernandezdevelasco influencesofthem2rgirk4rgs6dependentparasympatheticpathwayonelectrophysiologicalpropertiesofthemouseheart AT allisonanderson influencesofthem2rgirk4rgs6dependentparasympatheticpathwayonelectrophysiologicalpropertiesofthemouseheart AT kirillamartemyanov influencesofthem2rgirk4rgs6dependentparasympatheticpathwayonelectrophysiologicalpropertiesofthemouseheart AT kevinwickman influencesofthem2rgirk4rgs6dependentparasympatheticpathwayonelectrophysiologicalpropertiesofthemouseheart AT elenagtolkacheva influencesofthem2rgirk4rgs6dependentparasympatheticpathwayonelectrophysiologicalpropertiesofthemouseheart |
_version_ |
1724958462295670784 |