Two novel Brugada syndrome-associated mutations increase KV4.3 membrane expression and function

You,Tao; Mao,Weike; Cai,Benzhi; Li,Faqian; Xu,Haodong

doi:10.3892/ijmm.2015.2223

July-2015 Volume 36 Issue 1

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July-2015 Volume 36 Issue 1

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Article

Two novel Brugada syndrome-associated mutations increase KV4.3 membrane expression and function

Authors:
- Tao You
- Weike Mao
- Benzhi Cai
- Faqian Li
- Haodong Xu
View Affiliations / Copyright

Affiliations: Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R. China, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA
Pages: 309-315
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Published online on: May 26, 2015

https://doi.org/10.3892/ijmm.2015.2223
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Abstract

The human cardiac fast transient outward K+ channel is composed of the KV4.3 α subunit encoded by KCND3 and the K+ channel‑interacting protein 2 (KChIP2) β subunit, and determines the early repolarization of the action potential (AP). Two human mutations (G600R and L450F) in KV4.3 are associated with Brugada syndrome and they increase the KV4.3/KChIP2‑encoded fast transient outward K+ current (Ito,f) and cause the stable loss of the AP dome. However, the detailed mechanisms underlying the gain of Ito,f function by these two mutations are largely unknown. The experiments in the present study were undertaken to investigate the effect of these mutations and the underlying mechanism. Whole cell patch‑clamp recording was performed in HEK‑293 cells expressing KV4.3‑wild‑type (WT) and KV4.3 mutants with KChIP2. The two individual mutant‑encoded currents were significantly increased but the kinetics of the channels affected by the two mutations were different. The two mutations slowed KV4.3/KChIP2‑encoded channel inactivation; they did not increase the recovery from the KV4.3/KChIP2‑encoded channel inactivation. Western blotting showed that total KV4.3 protein was significantly augmented in HEK‑293 cells expressing the two individual mutants with KChIP2. Furthermore, immunofluorescence confocal microscopy demonstrated that the KV4.3 channel protein was expressed more in the cell membrane compared to the cytoplasm in cells that expressed individual mutants with KChIP2. Also, KChIP2 increased the amount of channel protein in the cell membrane of KV4.3 mutants significantly more than KV4.3‑WT. Reverse transcription‑polymerase chain reaction showed that KV4.3 mRNA was not significantly changed by individual mutations in the presence of KChIP2. Taken together, the present study revealed that the mutations cause a gain‑of‑function of KV4.3/KChIP2‑encoded channels by increasing membrane protein expression and slowing channel inactivation.

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Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Two novel Brugada syndrome-associated mutations increase KV4.3 membrane expression and function

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