Role of HCN4 channel in preventing ventricular arrhythmia.
Bradycardia is a trigger of ventricular arrhythmias in patients with arrhythmia including Brugada syndrome and long QT syndrome. The HCN4 channel controls the heart rate, and its mutations predispose to inherited sick sinus syndrome and long QT syndrome associated with bradycardia. We found a 4 base-insertion at the splice donor site of the HCN4 gene in a patient with idiopathic ventricular tachycardia, which was supposed to generate a truncated channel. To investigate the role of the HCN4 channel in ventricular arrhythmia, we introduced a ventricular action potential of I(f) channel produced by HCN4 in a computer simulation model and found that the I(f) channel generated a leaky outward current during the plateau phase of ventricular action potential. Currents through the I(f) channel were suggested to contribute to the shortening of the action potential duration and the prevention of early after-depolarization in bradycardia. These observations suggested that the HCN4 channel played a preventive role in triggering bradycardia-induced ventricular arrhythmias.
Ueda
Kazuo
K
Department of Molecular Pathogenesis, Tokyo Medical and Dental University, Tokyo, Japan.
Hirano
Yuji
Y
Higashiuesato
Yasushi
Y
Aizawa
Yoshiyasu
Y
Hayashi
Takeharu
T
Inagaki
Natsuko
N
Tana
Takeshi
T
Ohya
Yusuke
Y
Takishita
Shuichi
S
Muratani
Hiromi
H
Hiraoka
Masayasu
M
Kimura
Akinori
A
D000200:Action Potentials; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D001483:Base Sequence; D003198:Computer Simulation; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000235:genetics*; D006352:Heart Ventricles / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D015640:Ion Channel Gating; D008954:Models, Biological; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D015221:Potassium Channels; D012326:RNA Splicing / Q000235:genetics
D054815:Cyclic Nucleotide-Gated Cation Channels; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009124:Muscle Proteins; D015221:Potassium Channels