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 (I), which is important for determining the repolarization of action potential in the cardiac atrium. However, the expression of I is reduced in patients with chronic atrial fibrillation. 4-Aminopyridine (4-AP) can specifically suppress I, 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 in patients with chronic atrial fibrillation.