Regulation of Cardiac Conduction and Arrhythmias by Ankyrin/Spectrin-Based Macromolecular Complexes

Abstract

The cardiac conduction system is an extended network of excitable tissue tasked with generation and propagation of electrical impulses to signal coordinated contraction of the heart. The fidelity of this system depends on the proper spatio-temporal regulation of ion channels in myocytes throughout the conduction system. Importantly, inherited or acquired defects in a wide class of ion channels has been linked to dysfunction at various stages of the conduction system resulting in life-threatening cardiac arrhythmia. There is growing appreciation of the role that adapter and cytoskeletal proteins play in organizing ion channel macromolecular complexes critical for proper function of the cardiac conduction system. In particular, members of the ankyrin and spectrin families have emerged as important nodes for normal expression and regulation of ion channels in myocytes throughout the conduction system. Human variants impacting ankyrin/spectrin function give rise to a broad constellation of cardiac arrhythmias. Furthermore, chronic neurohumoral and biomechanical stress promotes ankyrin/spectrin loss of function that likely contributes to conduction disturbances in the setting of acquired cardiac disease. Collectively, this review seeks to bring attention to the significance of these cytoskeletal players and emphasize the potential therapeutic role they represent in a myriad of cardiac disease states.

Late Sodium Current of the Heart: Where Do We Stand and Where Are We Going?

“…This observation was confirmed by the same team in cultured cells [220]. Ranolazine is an antiarrhythmic drug inhibiting late sodium current with high selectivity over the transient phase [20,51,52,154,221]. Considering that myocardial wall stretch has been linked to clinical arrhythmias for a long time [222][223][224], these data may help to develop new therapeutic strategies in the antiarrhythmic pharmacology.…”

“…Several proteins have been shown to interact with the pore-forming subunit of VGSC, including the ß-subunits [225][226][227], small G-proteins [228], Ankyrin G [221], SAP97 [229], and ubiquitin [230]. Accessory proteins fulfill various functions during the life cycle of sodium channels being partners in posttranslational trafficking, supporting the anchoring at the target position, modulating gating properties, and controlling channel internalization/degradation.…”

“…Recently, there was a boom in this field, resulting in numerous publications. Due to volume limit, we refer to excellent reviews published recently [221,231].…”

Identification of novel hypermethylated or hypomethylated CpG sites and genes associated with anthracycline-induced cardiomyopathy

“…Primarily found at the cardiomyocyte intercalated disc. Loss results in increased fibrosis and decreased heart function 66 cg18637832 2.99E−04 0.06 chr4:119890132 SYNPO2 Body Actin binding muscle protein. Localized at the Z-disc of skeletal muscle cells and cardiomyocytes 49 , 50 , 67 cg04297105 2.82E−05 0.06 chr2:103235258 SLC9A2 /NHE2 TSS1500 chr2:103235376–103236554 Na+ -H+ exchange (NHE) is a major mechanism by which the heart adapts to intracellular acidosis during ischemia and recovers from the acidosis after reperfusion 68 cg06802630 1.30E−04 0.06 chr5:322735 AHRR Body chr5:320788–323010 DNA methylation of the aryl hydrocarbon receptor repressor is associated with subclinical atherosclerosis 69 cg08053904 5.36E−05 0.06 chr16:20085897 GPR139 TSS1500 chr16:20084707–20085305 G-protein coupled receptors play a central physiological role in the regulation of cardiac function and are targeted for the treatment of hypertension and heart failure 70 cg04369835 3.26E−04 0.06 chr5:322705 AHRR Body chr5:320788–323010 As above 69 cg25752677 1.33E−04 0.05 chr16:56309206 GNAO1 …”

Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias

“…Similarly, AnkG is established as an adaptor protein that organizes, transports, and anchors Na v 1.5 to the actin/spectrin cytoskeleton [267][268][269]. In fact, the AnkyrinG-Na v 1.5 complex is believed to connect with the actin/α-spectrin cytoskeleton through CaMKIIβ IV -spectrin interaction where the latter acts as a CaMKII-anchoring protein and thereby orchestrating the whole macromolecular complex; however, no evidence of direct interaction between Na v 1.5 and β IV -spectrin has been found yet [255].…”