Coordinating electrical activity of the heart: ankyrin polypeptides in human cardiac disease

Abstract

Introduction Over the past ten years, ankyrin polypeptides have emerged as critical players in cardiac excitation-contraction coupling. Once thought to solely play only a structural role, loss-of-function variants in genes encoding ankyrin polypeptides have highlighted how this protein mediates the proper subcellular localization of the various electrical components of the excitation-contraction coupling machinery. A large body of evidence has revealed how the disruption of this localization is the primary cause of various cardiomyopathies, ranging from long QT syndrome 4, to sinus node disease, to more common forms of arrhythmias. Areas Covered This review details the varied roles that ankyrin polypeptides play in excitation-contraction coupling in the heart and the development of ankyrin-specific cardiomyopathies. It will further discuss how ankyrin polypeptides may be involved in structural and electrical remodeling of the heart, post-myocardial infarct. Attention is given to how ankyrin interactions with membrane bound ion channels may regulate these channels’ response to stimuli. Special attention is given to exciting new data, which may offer the potential for unique therapies, for not only combating heart disease, but which also holds promise for wider applications to various disease states. Expert Opinion The ankyrin family of adapter proteins is emerging as an intimate player in cardiac excitation-contraction coupling. Until recently, these proteins have gone largely unappreciated for their importance in proper cardiac function. New insights into how these proteins function within the heart are offering potentially new avenues for therapies against cardiomyopathy.

Comprehensive Analysis of the Transcriptome-Wide m6A Methylome of Heart via MeRIP After Birth: Day 0 vs. Day 7

“…It has been reported that some of these genes play an independent role in heart disease. For example, although variants of Ank2 are associated with arrhythmia syndromes ( 42 ), sinus node disease ( 43 ), structural heart disease ( 44 ), and sudden cardiac death ( 45 ), their roles in cardiac proliferation are still unknown. Cmya5, encoded myospryn, functions as a negative regulator in skeletal muscle regeneration by inhibiting calcineurin-dependent transcriptional activity ( 46 ).…”

The evolving role of ankyrin-B in cardiovascular disease

“…Within the heart, ankyrin-B (AnkB) and ankyrin-G (AnkG) are the major ankyrin gene products, although ankyrin-R (AnkR) isoforms have also been identified. 1, 2 AnkG functions in the targeting of voltage-gated sodium channel Na v 1.5 to the intercalated disc. Further, human variants in Na v 1.5 that block interaction with AnkG are associated with Brugada syndrome, an arrhythmia syndrome associated with ST segment elevation in precordial leads V1–V3 and susceptibility to sudden cardiac death.…”

Genetic Complexity of Sinoatrial Node Dysfunction

“…Two families characterized with severe SND were found to have ANK2 allele variants, making AnkB the first non-ion channel protein associated with human SND ( Curran and Mohler, 2011 ). Interestingly, individuals with AF have reduced levels of AnkB expression and increased levels of miR-34a (a microRNA associated with cardiac fibrosis).…”

“…Ank2 +/− mice had greater RR variability due to multiple competing pacemaker sites between the SAN and the AV junction, further highlighting the role of AnkB in cardiac automaticity, yet suggesting some unknown mechanisms of compensation ( Glukhov et al, 2010 ). SAN cells from Ank2 +/– mice showed reduction in membrane expression of NCX1, Na + -K + -ATPase (NKA), and voltage-dependent L-type calcium channel alpha1D subunit (Ca v 1.3), causing abnormal intracellular Na + and Ca 2+ cycling, which generated various cardiac arrhythmic events ( Curran and Mohler, 2011 ). Computational models have further analyzed the role of AnkB in the generation of lethal arrhythmias.…”