Axial tubule junctions control rapid calcium signaling in atria
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Axial tubule junctions control rapid calcium signaling in atria. / Brandenburg, Sören; Kohl, Tobias; Williams, George S B; Gusev, Konstantin; Wagner, Eva; Rog-Zielinska, Eva A; Hebisch, Elke; Dura, Miroslav; Didié, Michael; Gotthardt, Michael; Nikolaev, Viacheslav O; Hasenfuss, Gerd; Kohl, Peter; Ward, Christopher W; Lederer, W Jonathan; Lehnart, Stephan E.
in: J CLIN INVEST, Jahrgang 126, Nr. 10, 03.10.2016, S. 3999-4015.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Axial tubule junctions control rapid calcium signaling in atria
AU - Brandenburg, Sören
AU - Kohl, Tobias
AU - Williams, George S B
AU - Gusev, Konstantin
AU - Wagner, Eva
AU - Rog-Zielinska, Eva A
AU - Hebisch, Elke
AU - Dura, Miroslav
AU - Didié, Michael
AU - Gotthardt, Michael
AU - Nikolaev, Viacheslav O
AU - Hasenfuss, Gerd
AU - Kohl, Peter
AU - Ward, Christopher W
AU - Lederer, W Jonathan
AU - Lehnart, Stephan E
PY - 2016/10/3
Y1 - 2016/10/3
N2 - 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.
AB - 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.
U2 - 10.1172/JCI88241
DO - 10.1172/JCI88241
M3 - SCORING: Journal article
C2 - 27643434
VL - 126
SP - 3999
EP - 4015
JO - J CLIN INVEST
JF - J CLIN INVEST
SN - 0021-9738
IS - 10
ER -