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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 September 19, 2016
Citation Information: J Clin Invest. 2016;126(10):3999-4015. https://doi.org/10.1172/JCI88241.
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Research Article Cardiology Cell biology

Axial tubule junctions control rapid calcium signaling in atria

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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 1

Abundant AT structures rapidly activate Ca2+ release.

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Abundant AT structures rapidly activate Ca2+ release.
(A) Confocal live ...
(A) Confocal live imaging of di-8-ANEPPS–stained (di8) TAT structures visualized as skeletons (pink). N, nucleus. Scale bar: 10 μm. TAT component orientations (histogram) and Gaussian fitting show abundant AT (0°) versus sparse TT (90°) components (binning ± 20°). n = 36 AMs. (B) Comparison of ventricular versus atrial TAT network length normalized to cell area; TT and AT component abundance. n = 36 AMs and 25 VMs. (C) Illustration conceptualizing AT width (δ) measurements and calculated surface area (SA). L, length. AT width was determined from local STED signal distributions of optical cross sections (brackets) and is summarized in the bar graph. Scale bars: 200 nm. n = 27 VMs, 30 AMs. (D) Double-headed arrows indicate potential AT-TT connections; ET images and segmentation of longitudinally sectioned and (E) cross-sectioned AT structures. Scale bars: 200 nm. Color legend – red, AT-SR junctions ≤ 15nm in gap width and containing RyR2 densities; yellow, AT-SR junctions ≤ 20nm in gap width but lacking RyR2 densities; green, membrane area with no apparent junctions. AT-TT junction; for color rendering, see Supplemental Figure 4. Arrows indicate exemplary electron densities compatible with RyR2 channels. (F) Bar graphs comparing TT versus AT volume/surface area ratio and width. n = 13 TTs, 23 ATs. Data are representative of 3 hearts. (G and H) Confocal images of Cav3-, RyR2-, and Cav1.2-coimmunostained mouse and human AMs. Robust Cav3-labeled AT structures in human and mouse AMs. Scale bars: 10 μm, magnification ×4. Yellow brackets indicate regions magnified. (I) Image segmentation. (J) Box plots summarizing TAT-specific Cav1.2 cluster density; component-specific Cav1.2 cluster numbers. White boxes indicate the mean; boxes represent the 50th percentile and lower and upper SD, and whiskers represent the 10th and 90th percentiles. n = 17 AMs. (K) Confocal visualization (negative contrast) of AT structures for transversal line scanning (yellow triangles) of intracellular Ca2+ (fluo-4) magnification ×4: field potential–evoked Ca2+ transient activated via AT and subsurface (S) structures; black diamonds, off-membrane CY; F25, Ca2+ signal onset at 25% signal amplitude; F/F0, Normalized fluorescence intensity ratio indicated by look-up-table; N, nucleus. (L) Relative latency of early Ca2+ signal upstroke (dF/dt) for the indicated locations. Data are representative of 19 AMs. (M) Voltage-clamped AMs (1 mM EGTA) during Ca2+ transient activation. F25, Ca2+ signal onset during –75 to 0 mV depolarization. (N) Latency difference of Ca2+ signal upstroke (dF/dt). n = 15 AMs. *P < 0.05, **P < 0.01, and ***P < 0.001, by Student’s t test (A–F, K–N) and Mann-Whitney U test (J).

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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