Abstract
The atrial G protein-gated inwardly rectifying K+ (GIRK) channel is a critical mediator of parasympathetic influence on cardiac physiology. Here, we probed the details and relevance of the GIRK channel in mouse ventricle. mRNAs for the atrial GIRK channel subunits (GIRK1, GIRK4), M2 muscarinic receptor (M2R), and RGS6, a negative regulator of atrial GIRK-dependent signaling, were detected in mouse ventricle at relatively low levels. The cholinergic agonist carbachol (CCh) activated small GIRK currents in adult wild-type ventricular myocytes that exhibited relatively slow kinetics and low CCh sensitivity; these currents were absent in ventricular myocytes from Girk1−/− or Girk4−/− mice. While loss of GIRK channels attenuated the CCh-induced shortening of action potential duration and suppression of ventricular myocyte excitability, selective ablation of GIRK channels in ventricle had no effect on heart rate, heart rate variability, or electrocardiogram parameters at baseline or after CCh injection. Additionally, loss of ventricular GIRK channels did not impact susceptibility to ventricular arrhythmias. These data suggest that the mouse ventricular GIRK channel is a GIRK1/GIRK4 heteromer, and show that while it contributes to the cholinergic suppression of ventricular myocyte excitability, this influence does not substantially impact cardiac physiology or ventricular arrhythmogenesis in the mouse.
Highlights
Increased output of the parasympathetic branch of the autonomic nervous system leads to the slowing of heart rate (HR) and an increase in heart rate variability (HRV), an indicator of beat-to-beat fluctuations in HR1,2
Despite the contribution of gated inwardly rectifying K+ (GIRK) channels to the CCh-dependent acceleration of repolarization and decrease in ventricular myocyte excitability, ventricular GIRK-dependent signaling does not exert a significant impact on HR, HRV, or susceptibility to ventricular arrhythmias in mice
We found that GIRK1, GIRK4, M2R, and Regulator of G protein Signaling 6 (RGS6) mRNAs were all present in mouse ventricular tissue, but that the levels of all targets were lower (4- to 10-fold) than those found in mouse atrial tissue (Fig. 1)
Summary
Increased output of the parasympathetic branch of the autonomic nervous system leads to the slowing of heart rate (HR) and an increase in heart rate variability (HRV), an indicator of beat-to-beat fluctuations in HR1,2. ACh shortened action potential duration (APD) in human ventricular myocytes, in an atropine-sensitive manner[25]. This effect has been attributed to the activation of a GIRK www.nature.com/scientificreports/. We present functional evidence that the GIRK channel in ventricular myocytes is a GIRK1/GIRK4 heteromer, and that it mediates the impact of cholinergic signaling on APD and excitability of these cells. Despite the contribution of GIRK channels to the CCh-dependent acceleration of repolarization and decrease in ventricular myocyte excitability, ventricular GIRK-dependent signaling does not exert a significant impact on HR, HRV, or susceptibility to ventricular arrhythmias in mice
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