Long-term 4-AP treatment facilitates functional expression of human Kv1.5 channel

Yu Xie; Wei-Guang Ding; Yang Liu; Miao Yu; Xin Sun; Hiroshi Matsuura

doi:10.1016/j.ejphar.2018.12.022

Long-term 4-AP treatment facilitates functional expression of human Kv1.5 channel

Eur J Pharmacol. 2019 Feb 5:844:195-203. doi: 10.1016/j.ejphar.2018.12.022. Epub 2018 Dec 12.

Authors

Yu Xie¹, Wei-Guang Ding², Yang Liu³, Miao Yu³, Xin Sun³, Hiroshi Matsuura⁴

Affiliations

¹ Jinlin Provincial Key Laboratory of Molecular Geriatric Medicine, Beihua University, Jilin, China; Department of Physiology, Shiga University of Medical Science, Otsu, Japan.
² Department of Physiology, Shiga University of Medical Science, Otsu, Japan.
³ Jinlin Provincial Key Laboratory of Molecular Geriatric Medicine, Beihua University, Jilin, China.
⁴ Department of Physiology, Shiga University of Medical Science, Otsu, Japan. Electronic address: matuurah@belle.shiga-med.ac.jp.

PMID: 30552904
DOI: 10.1016/j.ejphar.2018.12.022

Abstract

The human Kv1.5 channel (hKv1.5) produces the ultrarapid delayed rectifier potassium current (I_Kur), which is important for determining the repolarization of action potential in the cardiac atrium. However, the expression of I_Kur is reduced in patients with chronic atrial fibrillation. 4-Aminopyridine (4-AP) can specifically suppress I_Kur, suggesting that it modifies hKv1.5 as a chaperone molecule. Herein, the effects of long-term 4-AP treatment on hKv1.5 protein expression and function were investigated in HEK cells. 4-AP treatment (24 h) improved hKv1.5 protein levels, promoted hKv1.5 glycosylation, and facilitated the hKv1.5 current in a time-dependent manner. Long-term 4-AP treatment also markedly enhanced hKv1.5 localization in the cell membrane, endoplasmic reticulum, and Golgi. Importantly, the Ile508 residue located in the hKv1.5 channel pore was found to be important for 4-AP inhibitory activity. These results provide insight into developing hKv1.5 channel blocker that can functionally rescue I_Kur in patients with chronic atrial fibrillation.

Keywords: Chaperone; Glycosylation; I(Kur); Rescue; Trafficking; hKv1.5 channel.

MeSH terms

4-Aminopyridine / pharmacology*
Glycosylation
HEK293 Cells
Humans
Kv1.5 Potassium Channel / physiology*
Potassium Channel Blockers / pharmacology*

Substances

KCNA5 protein, human
Kv1.5 Potassium Channel
Potassium Channel Blockers
4-Aminopyridine