Kv1.1 Potassium Channel Deficiency Prolongs Ventricular Action Potentials And Decreases Tachycardia Susceptibility
Authors: Trosclair Krystle , Si Man , Watts Megan , Dominic Paari , Hamilton Kathryn , Glasscock Edward 
Published: November 2023

Voltage‐gated Kv1.1 potassium channels, encoded by the Kcna1 gene, exhibit widespread expression throughout the central and peripheral nervous systems and their dysfunction leads to neurological diseases including epilepsy and episodic ataxia type 1. Mutations in Kcna1 have also been linked to sudden unexpected death in epilepsy (SUDEP) in both mice and humans. Kv1.1 channels have traditionally been regarded as predominantly neural‐specific with no known expression or function in the heart. However, recent studies in mice and humans reveal that Kv1.1 channels are expressed in cardiomyocytes and make an important and previously overlooked contribution to cardiac function, especially in atrial cardiomyocytes where Kcna1 gene deletion (KO) increases susceptibility to atrial arrhythmias in mice. In this work, the functional role of Kv1.1 channels in the ventricles was investigated for the first time using Kcna1 KO mice. To test susceptibility to ventricular arrhythmias, mice were subjected to intracardiac programmed electrical stimulation. In response to burst pacing, KO mice exhibited 80% lower incidence of inducible ventricular tachycardia at baseline and following administration of the β‐adrenergic agonist, isoproterenol. Next, whole‐cell patch clamp recordings were performed on isolated ventricular cardiomyocytes to measure the contribution of Kv1.1 channels to action potential morphology and outward K+ currents. In current clamp recordings, action potential duration was significantly prolonged in KO cells by about ~50% compared to WT, whereas in voltage clamp experiments, KO cells exhibited a ~50% reduction in outward K+ currents. However, application of the specific Kv1.1 channel blocker, dendrotoxin‐K, did not significantly reduce outward K+ currents in WT cells, suggesting a minimal contribution by Kv1.1 channels. Finally, to determine whether transcriptional channel remodeling contributes to the cardiac phenotypes in KO mice, mRNA levels of the main ventricular cardiac ion channels were measured using quantitative RT‐PCR (qPCR). qPCR revealed no drastic differences in ion channel expression between KO and WT mice at the level of mRNA suggesting the absence of Kv1.1 channels may be the primary molecular cause of the cardiac abnormalities. In summary, the decreased arrhythmia susceptibility and action potential prolongation in the ventricles of Kcna1 KO mice suggest that Kv1.1 channels are important for normal ventricular function and may regulate risk of SUDEP involving cardiac mechanisms. However, in ventricles, the overall low level of Kv1.1 expression, the lack of dendrotoxin‐K sensitive currents, and the absence of drastic transcriptional remodeling suggest Kv1.1 deficiency may have complex indirect effects such as translational or post‐translational channel remodeling that could underlie cardiac abnormalities.Support or Funding InformationThis work was supported by a grant from the National Institutes of Health (R00HL107641 to EG) and a LSUHSC‐Shreveport Malcolm Feist Postdoctoral Fellowship to MS.