Dysfunction in the beta II Spectrin-Dependent Cytoskeleton Underlies Human Arrhythmia

Article

关键词: RYANODINE RECEPTOR DISTRIBUTION;    SUDDEN CARDIAC DEATH;    ANKYRIN-B SYNDROME;    VENTRICULAR-TACHYCARDIA;    HEART-FAILURE;    NEONATAL CARDIOMYOCYTES;    DIFFERENTIAL REGULATION;    COMPLEX PROTEINS;    ALPHA-SPECTRIN;    CELL-ADHESION;   

DOI  :  10.1161/CIRCULATIONAHA.114.013708

来源: SCIE

【 摘 要 】

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 to cardiac pathologies, including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction and cardiac electric 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 beta II spectrin, an actin-associated molecule, is essential for the posttranslational targeting and localization of critical membrane proteins in heart. beta II spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/beta II spectrin interaction, leading to severe human arrhythmia phenotypes. Mice lacking cardiac beta II spectrin display lethal arrhythmias, aberrant electric and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, beta II spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes, including the Na/Ca exchanger, ryanodine receptor 2, ankyrin-B, actin, and alpha II spectrin. Finally, we observe accelerated heart failure phenotypes in beta II spectrin-deficient mice. Conclusions-Our findings identify beta II spectrin as critical for normal myocyte electric activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology.

【 授权许可】

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