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

The human Kv1.5 channel (hKv1.5) produces the ultrarapid delayed rectifier potassium current (IKur), which is important for determining the repolarization of action potential in the cardiac atrium. However, the expression of IKur is reduced in patients with chronic atrial fibrillation. 4-Aminopyridi...

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Bibliographic Details
Published in:European journal of pharmacology 2019-02, Vol.844, p.195-203
Main Authors: Xie, Yu, Ding, Wei-Guang, Liu, Yang, Yu, Miao, Sun, Xin, Matsuura, Hiroshi
Format: Article
Language:English
Subjects:
Chaperone
Glycosylation
hKv1.5 channel
IKur
Rescue
Trafficking
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Summary:The human Kv1.5 channel (hKv1.5) produces the ultrarapid delayed rectifier potassium current (IKur), which is important for determining the repolarization of action potential in the cardiac atrium. However, the expression of IKur is reduced in patients with chronic atrial fibrillation. 4-Aminopyridine (4-AP) can specifically suppress IKur, 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 IKur in patients with chronic atrial fibrillation.
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2018.12.022