The G-protein–gated K+ channel, IKACh, is required for regulation of pacemaker activity and recovery of resting heart rate after sympathetic stimulation
Open Access
- 15 July 2013
- journal article
- research article
- Published by Rockefeller University Press in The Journal of general physiology
- Vol. 142 (2), 113-126
- https://doi.org/10.1085/jgp.201310996
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
This publication has 48 references indexed in Scilit:
- Novel insights into the distribution of cardiac HCN channels: An expression study in the mouse heartJournal of Molecular and Cellular Cardiology, 2011
- A Coupled SYSTEM of Intracellular Ca2+Clocks and Surface Membrane Voltage Clocks Controls the Timekeeping Mechanism of the Heart’s PacemakerCirculation Research, 2010
- Development of the Pacemaker Tissues of the HeartCirculation Research, 2010
- Cholinergic receptor signaling modulates spontaneous firing of sinoatrial nodal cells via integrated effects on PKA-dependent Ca2+ cycling and IKAChAmerican Journal of Physiology-Heart and Circulatory Physiology, 2009
- Effects of muscarinic receptor stimulation on Ca2+ transient, cAMP production and pacemaker frequency of rabbit sinoatrial node cellsBasic Research in Cardiology, 2009
- Control of heart rate by cAMP sensitivity of HCN channelsProceedings of the National Academy of Sciences of the United States of America, 2009
- Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMPThe EMBO Journal, 2008
- HCN4 provides a ‘depolarization reserve’ and is not required for heart rate acceleration in miceThe EMBO Journal, 2007
- A guided tour into subcellular colocalization analysis in light microscopyJournal of Microscopy, 2006
- Distribution of the Muscarinic K+ Channel Proteins Kir3.1 and Kir3.4 in the Ventricle, Atrium, and Sinoatrial Node of HeartJournal of Histochemistry & Cytochemistry, 2001