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

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.