Rescue of mutated cardiac ion channels in inherited arrhythmia syndromes

Abstract

Inherited arrhythmia syndromes comprise an increasingly complex group of diseases involving mutations in multiple genes encoding ion channels, ion channel accessory subunits and channel interacting proteins, and various regulatory elements. These mutations serve to disrupt normal electrophysiology in the heart, leading to increased arrhythmogenic risk and death. These diseases have added impact as they often affect young people, sometimes without warning. Although originally thought to alter ion channel function, it is now increasingly recognized that mutations may alter ion channel protein and messenger RNA processing, to reduce the number of channels reaching the surface membrane. For many of these mutations, it is also known that several interventions may restore protein processing of mutant channels to increase their surface membrane expression toward normal. In this article, we reviewed inherited arrhythmia syndromes, focusing on long QT syndrome type 2, and discuss the complex biology of ion channel trafficking and pharmacological rescue of disease-causing mutant channels. Pharmacological rescue of misprocessed mutant channel proteins, or their transcripts providing appropriate small molecule drugs can be developed, has the potential for novel clinical therapies in some patients with inherited arrhythmia syndromes.

FIGURE 1.

Major currents underlying the cardiac ventricular action potential. A simulated electrocardiogram is shown above the action potential waveform and major individual currents. I_Na, sodium current; I_Ca, L-type calcium current; I_to1, transient outward current 1; I_to2, transient outward current 2; I_K1, inward rectifier potassium current; I_Kr, rapidly activating delayed rectifier potassium current; I_Ks, slowly activating delayed rectifier potassium current; I_NaCa, sodium–calcium exchanger current; I_f, pacemaker current. For current traces, dotted line is zero current. Modified from He et al.

FIGURE 2.

A proposed trafficking model for hERG K⁺ channels. A, Protein pathway for synthesis, recycling, and degradation. Dashed arrow indicates a nonconventional pathway. B, Disease mechanisms in LQT2.

FIGURE 3.

A structural model of the a-subunit of hERG protein showing localization of 39 missense mutations or putative polymorphisms. See text for description and discussion. Modified from Anderson et al.