Dysfunction in the βII Spectrin–Dependent Cytoskeleton Underlies Human Arrhythmia

Abstract

Background The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease. In fact, human mutations in cardiac cytoskeletal elements are tightly linked with cardiac pathologies including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction in cardiac electrical activity is not well understood, and often overlooked in the cardiac arrhythmia field. Methods and Results Here, we uncover a new mechanism for the regulation of cardiac membrane excitability. We report that βII spectrin, an actin-associated molecule, is essential for the post-translational targeting and localization of critical membrane proteins in heart. βII spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/βII spectrin interaction leading to severe human arrhythmia phenotypes. Mice lacking cardiac βII spectrin display lethal arrhythmias, aberrant electrical and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, βII spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes that include the Na/Ca exchanger, RyR2, ankyrin-B, actin, and αII spectrin. Finally, we observe accelerated heart failure phenotypes in βII spectrin-deficient mice. Conclusions Our findings identify βII spectrin as critical for normal myocyte electrical activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology.

The role of βII spectrin in cardiac health and disease

“…This domain serves as a ligand binding site for many phospholipids involved in signal transduction [28,50,53–56]. Immunofluorescence staining shows that βII spectrin is localized in a striated pattern in isolated mouse myocytes [20]. …”

“…Disorders in cardiac cytoskeletal components have been strongly associated with cardiac myopathies, dystrophies, aortopathies and electrical conduction abnormalities [20,58–61]. While βII spectrin has a prominent role in many organ systems (Table 1), it has also emerged as a pivotal protein in maintaining normal cardiac membrane excitability, mechanical function [20] and proper embryogenesis [62]. …”

“…Until recently, arrhythmogenic cardiomyopathies were mainly linked to disorders in ion channels [83], however, little was known about arrhythmia resulting from defects in cytoskeletal-associated proteins [20]. Recent data reveal that defects in the βII spectrin-based cytoskeleton disrupt normal electrical conduction in the heart [20], potentially leading to congenital as well as acquired human arrhythmia [21].…”

“…Recent data reveal that defects in the βII spectrin-based cytoskeleton disrupt normal electrical conduction in the heart [20], potentially leading to congenital as well as acquired human arrhythmia [21]. …”

“…βII spectrin is critical in posttranslational targeting and localization of essential membrane proteins [15–17], plays a prominent role in signal transduction [18,19], and notably serves as a major scaflolding protein [2]. Defects in βII spectrin have been associated with serious cardiac pathologies such as congenital arrhythmia, acquired and congenital forms of heart failure, and possibly sudden cardiac death [20–23]. This review focuses on the recent advances in defining the role of βII spectrin in the cardiovascular system in physiologic and pathologic states.…”