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; Důra, Miroslav; Didié, Michael; Gotthardt, Michael; Nikolaev, Viacheslav O.; Hasenfuß, Gerd; Kohl, Peter; Ward, Christopher W.; Lederer, W. Jonathan; Lehnart, Stephan E.

doi:10.1172/jci88241

Cited by 115 publications

(220 citation statements)

References 53 publications

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“…To investigate the orientation of TATs, we combined image skeletonization and directionality analysis as previously described [32, 33] (see example of image processing in Supplementary Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

“…Tubule fragments at 0° are parallel with the longitudinal axis of the cell, while tubules at 90° are perpendicular. We considered tubules oriented at 0° ± 20° angles as axial tubules (AT) and those oriented at 90° ± 20° angles as transverse tubules (TT), as defined previously [33]. We found that in ventricular cells, there were more transverse components than axial components.…”

Section: Resultsmentioning

confidence: 99%

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Heterogeneity of transverse-axial tubule system in mouse atria: Remodeling in atrial-specific Na + –Ca 2+ exchanger knockout mice

Yue

Zhang

Kim

et al. 2017

Journal of Molecular and Cellular Cardiology

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Transverse-axial tubules (TATs) are commonly assumed to be sparse or absent in atrial myocytes from small animals. Atrial myocytes from rats, cats and rabbits lack TATs, which results in a characteristic “V”-shaped Ca release pattern in confocal line-scan recordings due to the delayed rise of Ca in the center of the cell. To examine TAT expression in isolated mouse atrial myocytes, we loaded them with the membrane dye Di-4-ANEPPS to label TATs. We found that >80% of atrial myocytes had identifiable TATs. Atria from male mice had a higher TAT density than female mice, and TAT density correlated with cell width. Using the fluorescent Ca indicator Fluo-4-AM and confocal imaging, we found that wild type (WT) mouse atrial myocytes generate near-synchronous Ca transients, in contrast to the “V”-shaped pattern typically reported in other small animals such as rat. In atrial-specific Na–Ca exchanger (NCX) knockout (KO) mice, which develop sinus node dysfunction and atrial hypertrophy with dilation, we found a substantial loss of atrial TATs in isolated atrial myocytes. There was a greater loss of transverse tubules compared to axial tubules, resulting in a dominance of axial tubules. Consistent with the overall loss of TATs, NCX KO atrial myocytes displayed a “V”-shaped Ca transient with slower and reduced central (CT) Ca re-lease and uptake in comparison to subsarcolemmal (SS) Ca release. We compared chemically detubulated (DT) WT cells to KO, and found similar slowing of CT Ca release and uptake. However, SS Ca transients in the WT DT cells had faster uptake kinetics than KO cells, consistent with the presence of NCX and normal sarcolemmal Ca efflux in the WT DT cells. We conclude that the remodeling of NCX KO atrial myocytes is accompanied by a loss of TATs leading to abnormal Ca release and uptake that could impact atrial contractility and rhythm.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Heterogeneity of transverse-axial tubule system in mouse atria: Remodeling in atrial-specific Na + –Ca 2+ exchanger knockout mice

Yue

Zhang

Kim

et al. 2017

Journal of Molecular and Cellular Cardiology

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“…The 3D electrical network of cardiomyocytes includes a finer order of complexity that involves a system of deep sarcolemmal membrane invaginations within each cell. As a network within a network, these sarcolemmal invaginations occur transversely with a periodicity roughly corresponding to that of sarcomere z-lines (transverse tubules, or T-tubules) and branch in the longitudinal direction (axial tubules) to form a complex system in atrial and ventricular cells, named the transverse-axial tubular system (TATS) (1,2). The TATS allows membrane potential changes to propagate rapidly into the cardiomyocyte core and is considered an ultimate structural player for excitation-contraction coupling.…”

mentioning

confidence: 99%

Quantitative assessment of passive electrical properties of the cardiac T-tubular system by FRAP microscopy

Scardigli

Crocini

Ferrantini

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Well-coordinated activation of all cardiomyocytes must occur on every heartbeat. At the cell level, a complex network of sarcolemmal invaginations, called the transverse-axial tubular system (TATS), propagates membrane potential changes to the cell core, ensuring synchronous and uniform excitation-contraction coupling. Although myocardial conduction of excitation has been widely described, the electrical properties of the TATS remain mostly unknown. Here, we exploit the formal analogy between diffusion and electrical conductivity to link the latter with the diffusional properties of TATS. Fluorescence recovery after photobleaching (FRAP) microscopy is used to probe the diffusion properties of TATS in isolated rat cardiomyocytes: A fluorescent dextran inside TATS lumen is photobleached, and signal recovery by diffusion of unbleached dextran from the extracellular space is monitored. We designed a mathematical model to correlate the time constant of fluorescence recovery with the apparent diffusion coefficient of the fluorescent molecules. Then, apparent diffusion is linked to electrical conductivity and used to evaluate the efficiency of the passive spread of membrane depolarization along TATS. The method is first validated in cells where most TATS elements are acutely detached by osmotic shock and then applied to probe TATS electrical conductivity in failing heart cells. We find that acute and pathological tubular remodeling significantly affect TATS electrical conductivity. This may explain the occurrence of defects in action potential propagation at the level of single T-tubules, recently observed in diseased cardiomyocytes.cardiac disease | transverse-axial tubular system | diffusion | electrical conductivity | porous rock T he sequential and coherent recruitment of all cardiomyocytes that occurs on every heartbeat is fundamental for proper contraction of the heart. Every heartbeat is triggered by a depolarizing event, the action potential (AP), spontaneously generated in cardiac pacemaker cells, which propagates through the conductive tissue and the working myocardium. The well-coordinated activation of all cardiomyocytes involves a spreading AP wave, conducted from cell to cell throughout the lattice of interconnections called gap junctions. The 3D electrical network of cardiomyocytes includes a finer order of complexity that involves a system of deep sarcolemmal membrane invaginations within each cell. As a network within a network, these sarcolemmal invaginations occur transversely with a periodicity roughly corresponding to that of sarcomere z-lines (transverse tubules, or T-tubules) and branch in the longitudinal direction (axial tubules) to form a complex system in atrial and ventricular cells, named the transverse-axial tubular system (TATS) (1, 2). The TATS allows membrane potential changes to propagate rapidly into the cardiomyocyte core and is considered an ultimate structural player for excitation-contraction coupling. During rapid depolarization, such as seen during the AP, Ca 2+ enters the cytos...

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“…82 For example, atrial cardiomyocytes have a less-developed t-tubular system. As such, it is likely that local signaling domains regulating G-protein signaling are also distinct between atrial and ventricular cardiomyocytes, 83 although this has not yet been extensively investigated.…”

Section: Future Perspectives Chamber-specific Regulation Of G-proteinmentioning

confidence: 99%

Regulation of heterotrimeric G-protein signaling by NDPK/NME proteins and caveolins: an update

Abu-Taha

Heijman

Feng

et al. 2018

Laboratory Investigation

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Heterotrimeric G proteins are pivotal mediators of cellular signal transduction in eukaryotic cells and abnormal G-protein signaling plays an important role in numerous diseases. During the last two decades it has become evident that the activation status of heterotrimeric G proteins is both highly localized and strongly regulated by a number of factors, including a receptor-independent activation pathway of heterotrimeric G proteins that does not involve the classical GDP/GTP exchange and relies on nucleoside diphosphate kinases (NDPKs). NDPKs are NTP/NDP transphosphorylases encoded by the nme/nm23 genes that are involved in a variety of cellular events such as proliferation, migration, and apoptosis. They therefore contribute, for example, to tumor metastasis, angiogenesis, retinopathy, and heart failure. Interestingly, NDPKs are translocated and/or upregulated in human heart failure. Here we describe recent advances in the current understanding of NDPK functions and how they have an impact on local regulation of G-protein signaling.

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Axial tubule junctions control rapid calcium signaling in atria

Cited by 115 publications

References 53 publications

Heterogeneity of transverse-axial tubule system in mouse atria: Remodeling in atrial-specific Na + –Ca 2+ exchanger knockout mice

Heterogeneity of transverse-axial tubule system in mouse atria: Remodeling in atrial-specific Na + –Ca 2+ exchanger knockout mice

Quantitative assessment of passive electrical properties of the cardiac T-tubular system by FRAP microscopy

Regulation of heterotrimeric G-protein signaling by NDPK/NME proteins and caveolins: an update

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