Cardiomyocyte protein trafficking: Relevance to heart disease and opportunities for therapeutic intervention

Abstract

Cardiomyocytes, the individual contractile units of heart muscle, are long-lived and robust. Given the longevity of these cells, it can be easy to overlook their dynamic intracellular environment that contain rapid protein movements and frequent protein turnover. Critical gene transcription and protein translation occur continuously, as well as trafficking and localization of proteins to specific functional zones of cell membrane. As heart failure becomes an increasingly important clinical entity, growing numbers of investigative teams are examining the cell biology of healthy and diseased cardiomyocytes. In this review, we introduce the major architectural structures and types of protein movements within cardiac cells, and then review recent studies that explore the regulation of such movements. We conclude by introducing current translational directions of the basic studies with a focus on novel areas of therapeutic development.

β‐adrenergic‐mediated dynamic augmentation of sarcolemmal CaV1.2 clustering and co‐operativity in ventricular myocytes

“…In cardiomyocytes, both of these scaffolding and transport elements have been postulated to play a role in Ca V 1.2 trafficking. There, a 'targeted delivery' model has been proposed for two channels: connexin 43 and Ca V 1.2 (Shaw et al, 2007;Hong et al, 2010;Chkourko et al, 2012;Hong et al, 2012;Xiao & Shaw, 2015). In this model, vesicular channel cargo enters the negative-end of the MT at the Golgi and is transported to defined delivery hubs at the plasma membrane where the MT plus-end binds to an anchor complex (Xiao & Shaw, 2015).…”

“…There, a 'targeted delivery' model has been proposed for two channels: connexin 43 and Ca V 1.2 (Shaw et al, 2007;Hong et al, 2010;Chkourko et al, 2012;Hong et al, 2012;Xiao & Shaw, 2015). In this model, vesicular channel cargo enters the negative-end of the MT at the Golgi and is transported to defined delivery hubs at the plasma membrane where the MT plus-end binds to an anchor complex (Xiao & Shaw, 2015). In the case of Ca V 1.2 channels, BIN1 is the anchor/hub which docks the MT plus-end, targeting the channels to the t-tubule membrane (Hong et al, 2010;Hong et al, 2012).…”

Rapid Turnover of the Cardiac L-Type CaV1.2 Channel by Endocytic Recycling Regulates Its Cell Surface Availability

“…Defective trafficking of the cardiac Ca V 1.2 channel protein has been linked to disorders including atrial fibrillation, heart failure, and Brugada syndrome ( Antzelevitch et al., 2007 , Basheer and Shaw, 2016 , Schotten et al., 2003 , Simms and Zamponi, 2012 , Xiao and Shaw, 2015 ). Thus, elucidation of the pathway by which Ca V 1.2 traffics to and from the plasma membrane is very relevant to understanding heart function and dysfunction.…”

Cytoskeleton Regulation of Ion Channels

“…Caution should be used in presuming trafficking involves forward trafficking only, and not considering potential intramembrane movements or internalization (retrograde trafficking) 9 . A thorough characterization of dynamics of protein trafficking in which forward, intramembrane, and retrograde trafficking are isolated and examined in dynamic detail will help elucidate the mechanisms by which βII-spectrin affects ion channel localization.…”