Document Detail

Kv1.1 potassium channel deficiency reveals brain-driven cardiac dysfunction as a candidate mechanism for sudden unexplained death in epilepsy.
MedLine Citation:
PMID:  20392939     Owner:  NLM     Status:  MEDLINE    
Mice lacking Kv1.1 Shaker-like potassium channels encoded by the Kcna1 gene exhibit severe seizures and die prematurely. The channel is widely expressed in brain but only minimally, if at all, in mouse myocardium. To test whether Kv1.1-potassium deficiency could underlie primary neurogenic cardiac dysfunction, we performed simultaneous video EEG-ECG recordings and found that Kcna1-null mice display potentially malignant interictal cardiac abnormalities, including a fivefold increase in atrioventricular (AV) conduction blocks, as well as bradycardia and premature ventricular contractions. During seizures the occurrence of AV conduction blocks increased, predisposing Kv1.1-deficient mice to sudden unexplained death in epilepsy (SUDEP), which we recorded fortuitously in one animal. To determine whether the interictal AV conduction blocks were of cardiac or neural origin, we examined their response to selective pharmacological blockade of the autonomic nervous system. Simultaneous administration of atropine and propranolol to block parasympathetic and sympathetic branches, respectively, eliminated conduction blocks. When administered separately, only atropine ameliorated AV conduction blocks, indicating that excessive parasympathetic tone contributes to the neurocardiac defect. We found no changes in Kv1.1-deficient cardiac structure, but extensive Kv1.1 expression in juxtaparanodes of the wild-type vagus nerve, the primary source of parasympathetic input to the heart, suggesting a novel site of action leading to Kv1.1-associated cardiac bradyarrhythmias. Together, our data suggest that Kv1.1 deficiency leads to impaired neural control of cardiac rhythmicity due in part to aberrant parasympathetic neurotransmission, making Kcna1 a strong candidate gene for human SUDEP.
Edward Glasscock; Jong W Yoo; Tim T Chen; Tara L Klassen; Jeffrey L Noebels
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  30     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-15     Completed Date:  2010-05-14     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5167-75     Citation Subset:  IM    
Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA.
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MeSH Terms
Anti-Arrhythmia Agents / pharmacology
Arrhythmias, Cardiac / drug therapy,  physiopathology*
Atrioventricular Block / drug therapy,  physiopathology
Atropine / pharmacology
Bradycardia / drug therapy,  physiopathology
Brain / physiopathology*
Electrocardiography / methods
Electroencephalography / methods
Heart / drug effects,  physiopathology*
Kv1.1 Potassium Channel / deficiency,  genetics,  metabolism*
Mice, Knockout
Parasympatholytics / pharmacology
Propranolol / pharmacology
Seizures / physiopathology*
Vagus Nerve / metabolism
Ventricular Premature Complexes / drug therapy,  physiopathology
Video Recording / methods
Grant Support
Reg. No./Substance:
0/Anti-Arrhythmia Agents; 0/Kcna1 protein, mouse; 0/Parasympatholytics; 147173-20-4/Kv1.1 Potassium Channel; 51-55-8/Atropine; 525-66-6/Propranolol
Comment In:
Auton Neurosci. 2012 Apr 3;167(1-2):1-3   [PMID:  22284814 ]

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