Functional Modifications of Ion Channels in Arrhythmogenesis

Cardiac ion channels control the flow of ions across the cell membrane and therefore are critical for heart rhythm and function. Therefore, they are heavily regulated by structural and/or functional modifications for the purposes of fine-tuning cardiac excitability and contraction under both physiologic and patho-physiologic mechanisms. Both the scale and type of modifications made to ion channels are numerous, contributing to a range of functional/regulatory changes. Among them, post-translational modifications, which are molecular changes to the primary amino acid structure of proteins, impacting characteristics ranging from protein trafficking, stability, localization, trafficking, kinetics, protein-protein interactions, and/or function have been identified as targets for channel regulation. Moreover, the molecular pathways underlying the gain and/or loss of function of ion channels are also important targets in the alteration of cardiac action potential and the generation of arrhythmia. Finally, the molecular pathways underlying the recruitment/activation of the enzymes and co-factors, which are essential to add or remove these modifications are also interestingly the target of significant regulation.

Here, we are looking to achieve a comprehensive overview of functional modifications targeting cardiac ion channels, the pathways that enact or remove these modifications, and importantly molecular interventions and/or therapies aimed at inducing/inhibiting these modifications for the treatment of heart disease and arrhythmia in particular. Historically, pharmacological anti-arrhythmic approaches targeting ion channel activity has paradoxically led to pro-arrhythmic outcomes. The expansion of our observations and understandings of these regulatory modifications and the development of pharmacological agents to manipulate their status, represent novel and important opportunities to achieve ion channel regulation and address the existing burdens for the management of heart disease and arrhythmia specifically, be it atrial or ventricular in origin. A comprehensive review of relevant players and existing or proposed strategies for targeted intervention will help to provide continued advancement of this opportunistic field and broader utility of mechanistically directed therapeutics.

Even within single ion channel genes, there can be a diverse array of modifications and specific target residues, satisfying different functional outcomes. Comprehensively identifying each of these modifications, their functional impacts, the regulation and recruitment of upstream pathways, the interaction within physiologic and pathologic signaling, and therapeutic potentials integrate a significant amount of information. Our scope is to compile a collection of research articles including original research, review articles and other types of articles, which focus on specific ion channels and the pathways/players which enact their functional modifications for patho-physiologic regulation. Alternatively, we encourage focusing on discrete regulatory pathways which may instead target several ion channel species. If possible, contributors are encouraged to discuss existing and/or potential interventions for regulation of ion channel modifications within the context of normal and/or disease status and the significance of those changes. The overall goal is to enhance further understanding of the mechanistic regulation and the significance of the ion channel functional modifications to feature them as novel therapeutic targets for the management of cardiac arrhythmia.