Axial tubule junctions control rapid calcium signaling in atria
Sören Brandenburg, … , W. Jonathan Lederer, Stephan E. Lehnart
Sören Brandenburg, … , W. Jonathan Lederer, Stephan E. Lehnart
Published October 3, 2016; First published September 19, 2016
Citation Information: J Clin Invest. 2016;126(10):3999-4015. https://doi.org/10.1172/JCI88241.
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Categories: Research Article Cardiology Cell biology

Axial tubule junctions control rapid calcium signaling in atria

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.

Authors

Sören Brandenburg, Tobias Kohl, George S.B. Williams, Konstantin Gusev, Eva Wagner, Eva A. Rog-Zielinska, Elke Hebisch, Miroslav Dura, Michael Didié, Michael Gotthardt, Viacheslav O. Nikolaev, Gerd Hasenfuss, Peter Kohl, Christopher W. Ward, W. Jonathan Lederer, Stephan E. Lehnart

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Figure 7

Catecholaminergic RyR2 cluster recruitment regulates sarcomere shortening and atrial contractility.

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Catecholaminergic RyR2 cluster recruitment regulates sarcomere shortenin...
(A) Representative AM sarcomere length traces during unloaded shortening; colors at top indicate the different conditions; VMs were used as a reference. The same WT AM control trace (black) is presented twice for comparison. WT AMs were treated with ISO (1 μM) or H89 (1 μM) and compared with RyR2-S2808A+/+-knockin, RyR2-S2814A+/+–knockin, or PLN-KO (Pln–/–) strains. Bar graphs summarizing maximal sarcomere shortening amplitude and velocity (Vmax) for the indicated conditions. Data are representative of 29 VMs and 59 AM WT controls; ISO, 13 AMs; H89, 33 AMs; S2808A, 44 AMs; S2814A, 36 AMs; and PLN, 17 AMs. *P < 0.05, **P < 0.01, and ***P < 0.001, by Student’s t test. (B) LA echocardiogram showing normal LA diameters in diastole versus systole (arrows) but significantly decreased fractional shortening in RyR2-S2808A+/+ mice. An electrocardiogram (ECG) recording (green) was used to time maximal atrial relaxation and contraction (triangles). n = 18 WT mice and 19 RyR2-S2808A mice+⁄+. *P < 0.05, by Student’s t test. Ao, aorta; asterisk indicates the aortic valve. Scale bars: 1 mm. (C) Confocal live-image overlays were aligned to the left-most striation as indicated. The flexible nature of the sarcomeric M-bands was visualized during AM contraction (red) versus relaxation (green) using knockin mice expressing C-terminal–tagged titin-EGFP and peripheral versus central readouts as indicated. Bar graphs summarize the relative M-band latency between peripheral (P) versus central (C) M-band regions in control- versus ISO-treated (1 μM) cells. n = 29 control and 24 ISO AMs. ***P < 0.001, by Student’s t test.