Scientific article
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English

The G-protein-gated K+ channel, IKACh, is required for regulation of pacemaker activity and recovery of resting heart rate after sympathetic stimulation

Published inThe Journal of general physiology, vol. 142, no. 2, p. 113-126
Publication date2013-08
First online date2013-07-15
Abstract

Parasympathetic regulation of sinoatrial node (SAN) pacemaker activity modulates multiple ion channels to temper heart rate. The functional role of the G-protein-activated K(+) current (IKACh) in the control of SAN pacemaking and heart rate is not completely understood. We have investigated the functional consequences of loss of IKACh in cholinergic regulation of pacemaker activity of SAN cells and in heart rate control under physiological situations mimicking the fight or flight response. We used knockout mice with loss of function of the Girk4 (Kir3.4) gene (Girk4(-/-) mice), which codes for an integral subunit of the cardiac IKACh channel. SAN pacemaker cells from Girk4(-/-) mice completely lacked IKACh. Loss of IKACh strongly reduced cholinergic regulation of pacemaker activity of SAN cells and isolated intact hearts. Telemetric recordings of electrocardiograms of freely moving mice showed that heart rate measured over a 24-h recording period was moderately increased (10%) in Girk4(-/-) animals. Although the relative extent of heart rate regulation of Girk4(-/-) mice was similar to that of wild-type animals, recovery of resting heart rate after stress, physical exercise, or pharmacological β-adrenergic stimulation of SAN pacemaking was significantly delayed in Girk4(-/-) animals. We conclude that IKACh plays a critical role in the kinetics of heart rate recovery to resting levels after sympathetic stimulation or after direct β-adrenergic stimulation of pacemaker activity. Our study thus uncovers a novel role for IKACh in SAN physiology and heart rate regulation.

Keywords
  • Acetylcholine / pharmacology
  • Action Potentials
  • Animals
  • Electrocardiography
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / genetics
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism
  • Heart Rate
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardial Reperfusion
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / physiology
  • Physical Exertion
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Sinoatrial Node / cytology
  • Sinoatrial Node / drug effects
  • Sinoatrial Node / innervation
  • Sinoatrial Node / physiology
  • Stress, Physiological
  • Sympathetic Nervous System / physiology
Affiliation entities Not a UNIGE publication
Citation (ISO format)
MESIRCA, Pietro et al. The G-protein-gated K+ channel, IKACh, is required for regulation of pacemaker activity and recovery of resting heart rate after sympathetic stimulation. In: The Journal of general physiology, 2013, vol. 142, n° 2, p. 113–126. doi: 10.1085/jgp.201310996
Main files (1)
Article (Published version)
Secondary files (10)
Identifiers
ISSN of the journal0022-1295
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