Mutant
KCNJ3
and
KCNJ5
Potassium Channels as Novel Molecular Targets in Bradyarrhythmias and Atrial Fibrillation
Authors: Yamada Noriaki , Asano Yoshihiro , Fujita Masashi , Yamazaki Satoru , Inanobe Atsushi , Matsuura Norio , Kobayashi Hatasu , Ohno Seiko , Ebana Yusuke , Tsukamoto Osamu , Ishino Saki , Takuwa Ayako , Kioka Hidetaka , Yamashita Toru , Hashimoto Norio , Zankov Dimitar P. , Shimizu Akio , Asakura Masanori , Asanuma Hiroshi , Kato Hisakazu , Nishida Yuya , Miyashita Yohei , Shinomiya Haruki , Naiki Nobu , Hayashi Kenshi , Makiyama Takeru , Ogita Hisakazu , Miura Katsuyuki , Ueshima Hirotsugu , Komuro Issei , Yamagishi Masakazu , Horie Minoru , Kawakami Koichi , Furukawa Tetsushi , Koizumi Akio , Kurachi Yoshihisa , Sakata Yasushi , Minamino Tetsuo , Kitakaze Masafumi , Takashima Seiji 
Published: February 2019

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. Because 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 7 individuals with autosomal dominant bradyarrhythmias of sinus node dysfunction, atrial fibrillation with slow ventricular response, and atrioventricular 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 upregulate heart rate in bradyarrhythmias by 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 (
I
KACh
channel) with specific expression in the atrium. An additional study using a genome cohort of 2185 patients with sporadic atrial fibrillation revealed another 5 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
I
KACh
channel function by increasing the basal current, even in the absence of m
2
muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant human
KCNJ3
in the atrium specifically. It is interesting to note that the selective
I
KACh
channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish.

Conclusions:

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