TitleNexilin Is a New Component of Junctional Membrane Complexes Required for Cardiac T-Tubule Formation
AuthorsLiu, Canzhao
Spinozzi, Simone
Chen, Zia-Yu
Fang, Xi
Feng, Wei
Perkins, Guy
Cattaneo, Paola
Guimaraes-Camboa, Nuno
Dalton, Nancy D.
Peterson, Kirk L.
Wu, Tongbin
Ouyang, Kunfu
Fu, Xiang-Dong
Evans, Sylvia M.
Chen, Ju
AffiliationUniv Calif, Dept Med, San Diego, CA USA
Univ Calif, Dept Cellular & Mol Med, San Diego, CA USA
Univ Calif, Natl Ctr Microscopy & Imaging Res, San Diego, CA USA
Univ Calif, Inst Genom Med, San Diego, CA USA
Univ Calif, Dept Pharmacol, Skaggs Sch Pharm & Pharmaceut Sci, San Diego, CA USA
Med Res, Milan, Italy
Humanitas Clin & Res Ctr, Rozzano, Italy
Goethe Univ Frankfurt, Ctr Mol Med, Inst Cardiovasc Regenerat, Frankfurt, Germany
German Ctr Cardiovasc Res DZHK, Berlin, Germany
Peking Univ, Shenzhen Grad Sch, Drug Discovery Ctr, State Key Lab Chem Oncogen,Sch Chem Biol & Biotec, Shenzhen, Peoples R China
junctional membrane complexes
membrane contact sites
Issue Date2019
AbstractBackground: Membrane contact sites are fundamental for transmission and translation of signals in multicellular organisms. The junctional membrane complexes in the cardiac dyads, where transverse (T) tubules are juxtaposed to the sarcoplasmic reticulum, are a prime example. T-tubule uncoupling and remodeling are well-known features of cardiac disease and heart failure. Even subtle alterations in the association between T-tubules and the junctional sarcoplasmic reticulum can cause serious cardiac disorders. NEXN (nexilin) has been identified as an actin-binding protein, and multiple mutations in the NEXN gene are associated with cardiac diseases, but the precise role of NEXN in heart function and disease is still unknown. Methods: Nexn global and cardiomyocyte-specific knockout mice were generated. Comprehensive phenotypic and RNA sequencing and mass spectrometry analyses were performed. Heart tissue samples and isolated single cardiomyocytes were analyzed by electron and confocal microscopy. Results: Global and cardiomyocyte-specific loss of Nexn in mice resulted in a rapidly progressive dilated cardiomyopathy. In vivo and in vitro analyses revealed that NEXN interacted with junctional sarcoplasmic reticulum proteins, was essential for optimal calcium transients, and was required for initiation of T-tubule invagination and formation. Conclusions: These results demonstrated that NEXN is a pivotal component of the junctional membrane complex and is required for initiation and formation of T-tubules, thus providing insight into mechanisms underlying cardiomyopathy in patients with mutations in NEXN.
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