PUBLICATION
Mutant KCNJ3 and KCNJ5 Potassium Channels as Novel Molecular Targets in Bradyarrhythmias and Atrial Fibrillation
- Authors
- Yamada, N., Asano, Y., Fujita, M., Yamazaki, S., Inanobe, A., Matsuura, N., Kobayashi, H., Ohno, S., Ebana, Y., Tsukamoto, O., Ishino, S., Takuwa, A., Kioka, H., Yamashita, T., Hashimoto, N., Zankov, D.P., Shimizu, A., Asakura, M., Asanuma, H., Kato, H., Nishida, Y., Miyashita, Y., Shinomiya, H., Naiki, N., Hayashi, K., Makiyama, T., Ogita, H., Miura, K., Ueshima, H., Komuro, I., Yamagishi, M., Horie, M., Kawakami, K., Furukawa, T., Koizumi, A., Kurachi, Y., Sakata, Y., Minamino, T., Kitakaze, M., Takashima, S.
- ID
- ZDB-PUB-190216-1
- Date
- 2019
- Source
- Circulation 139(18): 2157-2169 (Journal)
- Registered Authors
- Kawakami, Koichi
- Keywords
- IKACh channel blocker, KCNJ3, KCNJ5, acetylcholine-activated potassium channel (IKACh channel), bradyarrhythmia
- MeSH Terms
-
- Amino Acid Substitution
- Animals
- Animals, Genetically Modified
- Atrial Fibrillation*/genetics
- Atrial Fibrillation*/metabolism
- Atrial Fibrillation*/pathology
- Atrial Fibrillation*/physiopathology
- Atrioventricular Block*/genetics
- Atrioventricular Block*/metabolism
- Atrioventricular Block*/pathology
- Atrioventricular Block*/physiopathology
- Benzopyrans/pharmacology
- Bradycardia*/genetics
- Bradycardia*/metabolism
- Bradycardia*/pathology
- Bradycardia*/physiopathology
- Electrophysiologic Techniques, Cardiac
- Female
- G Protein-Coupled Inwardly-Rectifying Potassium Channels*/antagonists & inhibitors
- G Protein-Coupled Inwardly-Rectifying Potassium Channels*/genetics
- G Protein-Coupled Inwardly-Rectifying Potassium Channels*/metabolism
- Genetic Diseases, Inborn*/genetics
- Genetic Diseases, Inborn*/metabolism
- Genetic Diseases, Inborn*/pathology
- Genetic Diseases, Inborn*/physiopathology
- Humans
- Male
- Mutation, Missense*
- Xenopus laevis
- Zebrafish
- PubMed
- 30764634 Full text @ Circulation
Citation
Yamada, N., Asano, Y., Fujita, M., Yamazaki, S., Inanobe, A., Matsuura, N., Kobayashi, H., Ohno, S., Ebana, Y., Tsukamoto, O., Ishino, S., Takuwa, A., Kioka, H., Yamashita, T., Hashimoto, N., Zankov, D.P., Shimizu, A., Asakura, M., Asanuma, H., Kato, H., Nishida, Y., Miyashita, Y., Shinomiya, H., Naiki, N., Hayashi, K., Makiyama, T., Ogita, H., Miura, K., Ueshima, H., Komuro, I., Yamagishi, M., Horie, M., Kawakami, K., Furukawa, T., Koizumi, A., Kurachi, Y., Sakata, Y., Minamino, T., Kitakaze, M., Takashima, S. (2019) Mutant KCNJ3 and KCNJ5 Potassium Channels as Novel Molecular Targets in Bradyarrhythmias and Atrial Fibrillation. Circulation. 139(18):2157-2169.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping