Sakima A Smith1, Amy C Sturm1, Jerry Curran1, Crystal F Kline1, Sean C Little1, Ingrid M Bonilla1, Victor P Long1, Michael Makara1, Iuliia Polina1, Langston D Hughes1, Tyler R Webb1, Zhiyi Wei1, Patrick Wright1, Niels Voigt1, Deepak Bhakta1, Katherine G Spoonamore1, Chuansheng Zhang1, Raul Weiss1, Philip F Binkley1, Paul M Janssen1, Ahmet Kilic1, Robert S Higgins1, Mingzhai Sun1, Jianjie Ma1, Dobromir Dobrev1, Mingjie Zhang1, Cynthia A Carnes1, Matteo Vatta1, Matthew N Rasband1, Thomas J Hund1, Peter J Mohler2. 1. From Dorothy M. Davis Heart and Lung Research Institute (S.A.S., A.C.S., J.C., C.F.K., S.C.L., I.M.B., V.P.L., M.M., I.P., L.D.H., T.R.W., P.W., R.W., P.F.B., P.M.J., A.K., R.S.H., M.S., J.M., C.A.C., T.J.H., P.J.M.), Department of Internal Medicine, Division of Cardiovascular Medicine (S.A.S., R.W., P.F.B., P.J.M.), Department of Internal Medicine, Division of Human Genetics (A.C.S., P.M.J.), Department of Physiology and Cell Biology (J.C., C.F.K., S.C.L., M.M., I.P., L.D.H., T.R.W., P.W., P.M.J., P.J.M.), and Department of Surgery (A.K., R.S.H., M.S., J.M.), The Ohio State University Wexner Medical Center; Columbus; College of Pharmacy (I.M.B., V.P.L., C.A.C.) and Department of Biomedical Engineering, College of Engineering (T.J.H.), The Ohio State University, Columbus; Division of Life Science and Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay Kowloon, Hong Kong (Z.W., M.Z.); Department of Biology, South University of Science and Technology of China, Shenzhen, Guangdong, China (Z.W.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.); Krannert Institute of Cardiology and Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis (D.B., K.G.S., M.V.); and Department of Neuroscience, Baylor College of Medicine; Houston, TX (C.Z., M.N.R.). 2. From Dorothy M. Davis Heart and Lung Research Institute (S.A.S., A.C.S., J.C., C.F.K., S.C.L., I.M.B., V.P.L., M.M., I.P., L.D.H., T.R.W., P.W., R.W., P.F.B., P.M.J., A.K., R.S.H., M.S., J.M., C.A.C., T.J.H., P.J.M.), Department of Internal Medicine, Division of Cardiovascular Medicine (S.A.S., R.W., P.F.B., P.J.M.), Department of Internal Medicine, Division of Human Genetics (A.C.S., P.M.J.), Department of Physiology and Cell Biology (J.C., C.F.K., S.C.L., M.M., I.P., L.D.H., T.R.W., P.W., P.M.J., P.J.M.), and Department of Surgery (A.K., R.S.H., M.S., J.M.), The Ohio State University Wexner Medical Center; Columbus; College of Pharmacy (I.M.B., V.P.L., C.A.C.) and Department of Biomedical Engineering, College of Engineering (T.J.H.), The Ohio State University, Columbus; Division of Life Science and Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay Kowloon, Hong Kong (Z.W., M.Z.); Department of Biology, South University of Science and Technology of China, Shenzhen, Guangdong, China (Z.W.); Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany (N.V., D.D.); Krannert Institute of Cardiology and Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis (D.B., K.G.S., M.V.); and Department of Neuroscience, Baylor College of Medicine; Houston, TX (C.Z., M.N.R.). peter.mohler@osumc.edu.
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 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 βII spectrin, an actin-associated molecule, is essential for the posttranslational 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 electric 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, including the Na/Ca exchanger, ryanodine receptor 2, 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 electric activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology.
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 βII spectrin, an actin-associated molecule, is essential for the posttranslational 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 humanarrhythmia phenotypes. Mice lacking cardiac βII spectrin display lethal arrhythmias, aberrant electric 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, including the Na/Ca exchanger, ryanodine receptor 2, 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 electric activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology.
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Authors: Leigh Anne Swayne; Nathaniel P Murphy; Sirisha Asuri; Lena Chen; Xiaoxue Xu; Sarah McIntosh; Chao Wang; Peter J Lancione; Jason D Roberts; Charles Kerr; Shubhayan Sanatani; Elizabeth Sherwin; Crystal F Kline; Mingjie Zhang; Peter J Mohler; Laura T Arbour Journal: Circ Cardiovasc Genet Date: 2017-01
Authors: Sakima A Smith; Langston D Hughes; Crystal F Kline; Amber N Kempton; Lisa E Dorn; Jerry Curran; Michael Makara; Tyler R Webb; Patrick Wright; Niels Voigt; Philip F Binkley; Paul M L Janssen; Ahmet Kilic; Cynthia A Carnes; Dobromir Dobrev; Matthew N Rasband; Thomas J Hund; Peter J Mohler Journal: Am J Physiol Heart Circ Physiol Date: 2016-04-22 Impact factor: 4.733
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