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Axial tubule junctions control rapid calcium signaling in atria

Official URL:https://doi.org/10.1172/JCI88241
PubMed:View item in PubMed
Creators Name:Brandenburg, S. and Kohl, T. and Williams, G.S.B. and Gusev, K. and Wagner, E. and Rog-Zielinska, E.A. and Hebisch, E. and Dura, M. and Didie, M. and Gotthardt, M. and Nikolaev, V.O. and Hasenfuss, G. and Kohl, P. and Ward, C.W. and Lederer, W.J. and Lehnart, S.E.
Journal Title:Journal of Clinical Investigation
Journal Abbreviation:J Clin Invest
Volume:126
Number:10
Page Range:3999-4015
Date:3 October 2016
Abstract:The canonical atrial myocyte (AM) is characterized by sparse transverse tubule (TT) invaginations and slow intracellular Ca2+ propagation but exhibits rapid contractile activation that is susceptible to loss of function during hypertrophic remodeling. Here, we have identified a membrane structure and Ca2+-signaling complex that may enhance the speed of atrial contraction independently of phospholamban regulation. This axial couplon was observed in human and mouse atria and is composed of voluminous axial tubules (ATs) with extensive junctions to the sarcoplasmic reticulum (SR) that include ryanodine receptor 2 (RyR2) clusters. In mouse AM, AT structures triggered Ca2+ release from the SR approximately 2 times faster at the AM center than at the surface. Rapid Ca2+ release correlated with colocalization of highly phosphorylated RyR2 clusters at AT-SR junctions and earlier, more rapid shortening of central sarcomeres. In contrast, mice expressing phosphorylation-incompetent RyR2 displayed depressed AM sarcomere shortening and reduced in vivo atrial contractile function. Moreover, left atrial hypertrophy led to AT proliferation, with a marked increase in the highly phosphorylated RyR2-pS2808 cluster fraction, thereby maintaining cytosolic Ca2+ signaling despite decreases in RyR2 cluster density and RyR2 protein expression. AT couplon "super-hubs" thus underlie faster excitation-contraction coupling in health as well as hypertrophic compensatory adaptation and represent a structural and metabolic mechanism that may contribute to contractile dysfunction and arrhythmias.
ISSN:0021-9738
Publisher:American Society for Clinical Investigation (U.S.A.)
Item Type:Article

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