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Essential role of the m(2)R-RGS6-I-KACh pathway in controlling intrinsic heart rate variability

Academic Article
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Overview

authors

  • Posokhova, E.
  • Ng, D.
  • Opel, A.
  • Masuho, I.
  • Tinker, A.
  • Biesecker, L. G.
  • Wickman, K.
  • Martemyanov, Kirill

publication date

  • October 2013

journal

  • PLoS One  Journal

abstract

  • Normal heart function requires generation of a regular rhythm by sinoatrial pacemaker cells and the alteration of this spontaneous heart rate by the autonomic input to match physiological demand. However, the molecular mechanisms that ensure consistent periodicity of cardiac contractions and fine tuning of this process by autonomic system are not completely understood. Here we examined the contribution of the m2R-I(KACh) intracellular signaling pathway, which mediates the negative chronotropic effect of parasympathetic stimulation, to the regulation of the cardiac pacemaking rhythm. Using isolated heart preparations and single-cell recordings we show that the m2R-I(KACh) signaling pathway controls the excitability and firing pattern of the sinoatrial cardiomyocytes and determines variability of cardiac rhythm in a manner independent from the autonomic input. Ablation of the major regulator of this pathway, Rgs6, in mice results in irregular cardiac rhythmicity and increases susceptibility to atrial fibrillation. We further identify several human subjects with variants in the RGS6 gene and show that the loss of function in RGS6 correlates with increased heart rate variability. These findings identify the essential role of the m2R-I(KACh) signaling pathway in the regulation of cardiac sinus rhythm and implicate RGS6 in arrhythmia pathogenesis.

subject areas

  • Acetylcholine
  • Animals
  • Arrhythmias, Cardiac
  • Autonomic Nervous System
  • Electrocardiography
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Heart
  • Heart Rate
  • Humans
  • In Vitro Techniques
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation, Missense
  • Myocardium
  • RGS Proteins
  • Receptor, Muscarinic M2
  • Signal Transduction
  • Sinoatrial Node
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Identity

PubMed Central ID

  • PMC3812209

International Standard Serial Number (ISSN)

  • 1932-6203

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0076973

PubMed ID

  • 24204714
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Additional Document Info

start page

  • e76973

volume

  • 8

issue

  • 10

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