Ion channel traffic jams: the significance of trafficking deficiency in long QT syndrome

Abstract

A well-balanced ion channel trafficking machinery is paramount for the normal electromechanical function of the heart. Ion channel variants and many drugs can alter the cardiac action potential and lead to arrhythmias by interfering with mechanisms like ion channel synthesis, trafficking, gating, permeation, and recycling. A case in point is the Long QT syndrome (LQTS), a highly arrhythmogenic disease characterized by an abnormally prolonged QT interval on ECG produced by variants and drugs that interfere with the action potential. Disruption of ion channel trafficking is one of the main sources of LQTS. We review some molecular pathways and mechanisms involved in cardiac ion channel trafficking. We highlight the importance of channelosomes and other macromolecular complexes in helping to maintain normal cardiac electrical function, and the defects that prolong the QT interval as a consequence of variants or the effect of drugs. We examine the concept of "interactome mapping" and illustrate by example the multiple protein-protein interactions an ion channel may undergo throughout its lifetime. We also comment on how mapping the interactomes of the different cardiac ion channels may help advance research into LQTS and other cardiac diseases. Finally, we discuss how using human induced pluripotent stem cell technology to model ion channel trafficking and its defects may help accelerate drug discovery toward preventing life-threatening arrhythmias. Advancements in understanding ion channel trafficking and channelosome complexities are needed to find novel therapeutic targets, predict drug interactions, and enhance the overall management and treatment of LQTS patients.

Fig. 1. Long QT Syndrome (LQTS) Overview.

Illustrative ECGs adapted from public reservoirs JLNS, Jervell Lange-Nielsen; ATS, Andersen-Tawil Syndrome; TS, Timothy Syndrome. Genes related to the autosomal dominant Romano-Ward Syndrome are marked in purple and genes associated with the autosomal recessive form Jervell Lange-Nielsen (JLNS) are marked in blue. ϯ, suspected LQTS–related gene.

Fig. 2. Regulatory steps in the trafficking of cardiac ion channels.

a Gene transcription. b Protein folding and proper assembly. c Post-translational modification & glycosylation. d Anterograde vesicular trafficking along microtubule. e Membrane insertion. f Interactions with anchoring, scaffolding and ancillary proteins. g Retrograde vesicular trafficking along microtubule (internalization). h Recycling. i Proteasomal degradation. j Lysosomal degradation.

Fig. 3. ‘Channeling’ ion channel trafficking deficiency through iPSC technologies.

a Precision Medicine for modeling ion channel trafficking deficiency in LQTS using iPSC technology. b Refinements for iPSC technology to investigate LQTS.