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Circulation. 2019 Feb 15. doi: 10.1161/CIRCULATIONAHA.118.036761. [Epub ahead of print]

Mutant KCNJ3 and KCNJ5 Potassium Channels as Novel Molecular Targets in Bradyarrhythmias and Atrial Fibrillation.

Author information

1
Cardiovascular Medicine, Osaka University Graduate School of Medicine, Japan.
2
Osaka University Graduate School of Medicine, Japan.
3
Department of Cell Biology, National Cerebral and Cardiovascular Center, Japan.
4
Pharmacology, Osaka University Graduate School of Medicine, Japan.
5
Kyoto University Graduate School of Medicine, Japan.
6
Chubu University, Japan.
7
Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Japan.
8
Life Science and Bioethics Research Center, Tokyo Medical and Dental University, Japan.
9
Department of Medical Biochemistry, Osaka University Graduate School of Medicine, Japan.
10
Medicine, Osaka University Graduate School, Japan.
11
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Japan.
12
Pharmaceuticals Division, Nissan Chemical Corporation, Japan.
13
Pharmaceuticals Division, Nissan Chemical Industries, Ltd, Japan.
14
Molecular Medical Biochemistry, Shiga University of Medical Science, Japan.
15
Cardiovascular Division, Hyogo College of Medicine, Japan.
16
Department of Internal Medicine, Meiji University of Integrative Medicine, Japan.
17
Department of Cardiovascular Medicine, Shiga University of Medical Science, Japan.
18
Cardiology, Kanazawa University Graduate School of Medical Science, Japan.
19
Department of Cardiovascular Medicine, Kyoto University, Japan.
20
Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular Biology, Shiga University of Medical Science, Japan.
21
Department of Public Health, Shiga University of Medical Science, Japan.
22
Department of Cardiovascular Medicine, The University of Tokyo Hospital, Japan.
23
Cardiovascular and Internal Medicine, Kanazawa University Graduate School of Medicine, Japan.
24
Department of Cardiovascular and Respiratory, Shiga University of Medical Science, Japan.
25
Division of Molecular and Developmental Biology, National Institute of Genetics, Japan.
26
Bio-informational Pharmacology, Tokyo Medical and Dental University, Medical Research Institute, Japan.
27
Graduate School of Medicine, Osaka University, Japan.
28
Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Japan.
29
Department of Clinical Medicine and Development, National Cerebral and Cardiovascular Center Hospital, Osaka, Japan, JAPAN.

Abstract

BACKGROUND:

Bradyarrhythmia is a common clinical manifestation. Although the majority of cases are acquired, genetic analysis of families with bradyarrhythmia has identified a growing number of causative gene mutations. Since the only ultimate treatment for symptomatic bradyarrhythmia has been invasive surgical implantation of a pacemaker, the discovery of novel therapeutic molecular targets is necessary to improve prognosis and quality of life.

METHODS:

We investigated a family containing seven individuals with autosomal dominant bradyarrhythmias of sinus node dysfunction (SND), atrial fibrillation (AF) with slow ventricular response, and atrio-ventricular block (AV block). To identify the causative mutation, we conducted the family-based whole exome sequencing and genome-wide linkage analysis. We characterized the mutation-related mechanisms based on the pathophysiology in vitro. After generating a transgenic animal model to confirm the human phenotypes of bradyarrhythmia, we also evaluated the efficacy of a newly identified molecular-targeted compound to up-regulate heart rate in bradyarrhythmias using the animal model.

RESULTS:

We identified one heterozygous mutation, KCNJ3 c.247A>C, p.N83H, as a novel cause of hereditary bradyarrhythmias in this family. KCNJ3 encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded by KCNJ5) to form the acetylcholine-activated potassium channel ( IKACh channel) with specific expression in the atrium. An additional study using a genome cohort of 2185 patients with sporadic AF revealed another five rare mutations in KCNJ3 and KCNJ5, suggesting the relevance of both genes to these arrhythmias. Cellular electrophysiological studies revealed that the KCNJ3 p.N83H mutation caused a gain of IKACh channel function by increasing the basal current, even in the absence of m2 muscarinic receptor (m2R) stimulation. We generated transgenic zebrafish expressing mutant human KCNJ3 in the atrium specifically. Interestingly, the selective IKACh channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish.

CONCLUSIONS:

The IKACh channel is associated with the pathophysiology of bradyarrhythmia and AF, and the mutant IKACh channel ( KCNJ3 p.N83H) can be effectively inhibited by NIP-151, a selective IKACh channel blocker. Thus, the IKACh channel might be considered to be a suitable pharmacological target for bradyarrhythmia patients with a gain-of-function mutation in the IKACh channel.

KEYWORDS:

IKACh channel blocker; KCNJ3; KCNJ5; acetylcholine-activated potassium channel (IKACh channel); bradyarrhythmia

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