Ion Channel Macromolecular Complexes in Cardiomyocytes: Roles in Sudden Cardiac Death

Abstract

The movement of ions across specific channels embedded on the membrane of individual cardiomyocytes is crucial for the generation and propagation of the cardiac electrical impulse. Emerging evidence over the last 20 years strongly suggests that the normal electrical function of the heart is the result of dynamic interactions of membrane ion channels working in an orchestrated fashion as part of complex molecular networks. Such networks work together with exquisite temporal precision to generate each action potential and contraction. Macromolecular complexes play crucial roles in transcription, translation, oligomerization, trafficking, membrane retention, glycosylation, posttranslational modification, turnover, function and degradation of all cardiac ion channels known to date. In addition, the accurate timing of each cardiac beat and contraction demands, a comparable precision on the assembly and organizations of sodium, calcium and potassium channel complexes within specific subcellular microdomains, where physical proximity allows for prompt and efficient interaction. This review article, part of the Compendium on Sudden Cardiac Death, discusses the major issues related to the role of ion channel macromolecular assemblies in normal cardiac electrical function and the mechanisms of arrhythmias leading to sudden cardiac death. It provides an idea of how these issues are being addressed in the laboratory and in the clinic, which important questions remain unanswered, and what future research will be needed to improve knowledge and advance therapy.

Decreased inward rectifier potassium current IK1in dystrophin-deficient ventricular cardiomyocytes

“…Voltage-dependent ion channels in cardiomyocytes are not solely regulated by the transmembrane voltage, but also through interactions with numerous proteins organized in complex networks 11,12 . Such “ion channel multiprotein assemblies” comprising (but not limited to) anchoring proteins, adaptor proteins, regulatory proteins, and enzymes regulate the trafficking, expression, localization, and function of an associated channel.…”

Potassium Channels in Regulation of Vascular Smooth Muscle Contraction and Growth

“…Is this simply a matter of redundancy, or does the pattern of expression of these channels tune the electrophysiology of VSM cells in different vascular beds in ways that are not yet clear (Zhong et al, 2010)? Second, while it is clear that K + channels, like all ion channels, exist in multi-protein signaling domains (Abriel, Rougier, & Jalife, 2015; Kim & Oh, 2016; Levitan, 2006), our understanding of the regional heterogeneity in the nature and composition of these signaling domains in different vascular beds is incomplete. Finally, our understanding of the regulation of expression and function of K + channels in major cardiovascular disease states also remains incomplete, particularly as they relate to different vascular beds around the body.…”

Cardiac Na Channels

“…There is also a growing literature on how posttranslational modifications of Na V 1.5 are facilitated through the presence of macromolecular complexes that allow selective and specific protein modification to confer functional effects (Abriel, Rougier, &Jalife, 2015). Multiple phosphorylation mechanisms through a variety of kinase pathways as well as glycosylation, arginine methylation, S-nitrosylation, ubiquitylation, and ion homeostatic mechanisms are all implicated as functional regulators of Na V 1.5 (Marionneau & Abriel, 2015).…”