Atrial GIRK channels mediate the effects of vagus nerve stimulation on heart rate dynamics and arrhythmogenesis

Steven W. Lee, Allison Anderson, Pilar A. Guzman, Atsushi Nakano, Elena G. Tolkacheva, Kevin Wickman

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23 Scopus citations


Diminished parasympathetic influence is central to the pathogenesis of cardiovascular diseases, including heart failure and hypertension. Stimulation of the vagus nerve has shown promise in treating cardiovascular disease, prompting renewed interest in understanding the signaling pathway(s) that mediate the vagal influence on cardiac physiology. Here, we evaluated the contribution of G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels to the effect of vagus nerve stimulation (VNS) on heart rate (HR), HR variability (HRV), and arrhythmogenesis in anesthetized mice. As parasympathetic fibers innervate both atria and ventricle, and GIRK channels contribute to the cholinergic impact on atrial and ventricular myocytes, we collected in vivo electrocardiogram recordings from mice lacking either atrial or ventricular GIRK channels, during VNS. VNS decreased HR and increased HRV in control mice, in a muscarinic receptor-dependent manner. This effect was preserved in mice lacking ventricular GIRK channels, but was nearly completely absent in mice lacking GIRK channels in the atria. In addition, atrial-specific ablation of GIRK channels conferred resistance to arrhythmic episodes induced by VNS. These data indicate that atrial GIRK channels are the primary mediators of the impact of VNS on HR, HRV, and arrhythmogenesis in the anesthetized mouse.

Original languageEnglish (US)
Article number943
JournalFrontiers in Physiology
Issue numberJUL
StatePublished - Jul 19 2018

Bibliographical note

Funding Information:
The authors would like to thank Dr. Bruce H. KenKnight, an employee of LivaNova, PLC (formerly Cyberonics, Inc.), for providing vagus nerve electrodes and pulse generators. This work was supported by grants to ET from the National Science Foundation (CAREER PHY-125541 and DCSD 1662250), as well as the following grants and fellowships from the National Heart, Lung, and Blood Institute of the National Institutes of Health: F31 HL129544 (SWL), F31 HL139090 (AA), R21 HL124503 (AN), R21 HL128790 (ET), and R01 HL10 5550 (KW).

Publisher Copyright:
© 2018 Lee, Anderson, Guzman, Nakano, Tolkacheva and Wickman.


  • Arrhythmogenesis
  • Atrial
  • GIRK channel
  • Kir3
  • Parasympathetic
  • Vagus nerve stimulation


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