Ion channel trafficking: a new therapeutic horizon for atrial fibrillation

Abstract

Atrial fibrillation (AF) is a common cardiac arrhythmia with potentially life-threatening complications. Drug therapies for treatment of AF that seek long-term maintenance of normal sinus rhythm remain elusive due in large part to proarrhythmic ventricular actions. Kv1.5, which underlies the atrial specific I(Kur) current, is a major focus of research efforts seeking new therapeutic strategies and targets. Recent work has shown a novel effect of antiarrhythmic drugs where compounds that block Kv1.5 channel current also can alter ion channel trafficking. This work further suggests that the pleiotropic effects of antiarrhythmic drugs may be separable. Although this finding highlights the therapeutic potential for selective manipulation of ion channel surface density, it also reveals an uncertainty regarding the specificity of modulating trafficking pathways without risk of off-target effects. Future studies may show that specific alteration of Kv1.5 trafficking can overcome the proarrhythmic limitations of current pharmacotherapy and provide an effective method for long-term cardioversion in AF.

Figure 1

Potential therapeutic intervention points in the trafficking of membrane proteins. Each arrow represents a regulatory step in the trafficking of membrane proteins that could serve as a potential therapeutic target for modulating steady-state cells surface levels of ion channels. The left half of this figure represents an area where much work has been done in the hERG field for the treatment of LQTS and other arrhythmias. The right half represents and exciting developing field for the regulation of Kv1.5 membrane levels in the treatment of atrial fibrillation. Endoplasmic Reticulum (ER); Recycling Endosome (RE); Late Endosome (LE).

Figure 2

Antiarrhythmic drug-induced internalization of atrial specific Kv1.5 as a novel therapeutic target for AF. (A) Drug-induced internalization is specific to the atrial potassium channel Kv1.5. (B) Kv1.5 specific internalization results in a decrease in I_Kur density. (C) Decreased I_Kur may result in an increase in atrial, not ventricular, action potential duration. (D) Increased atrial action potential duration may terminate atrial fibrillation and restore normal sinus node rhythm control.

Figure 3

Strategies to isolate drug-induced internalization from pore block. Cartoon representation of the potential drug binding site of the Kv1.5 channel pore. (1) Ion channel mutagenesis can be used to fully characterize the incomplete overlap in the drug binding site for pore block and channel internalization. (2) Multiple moieties within the quinidine molecule can be studied in structure activity analysis to identify the pharmacophore for drug-induced internalization.