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1
Frisk, Michael, Jussi T. Koivumäki, Per A. Norseng, Mary M. Maleckar, Ole M. Sejersted und William E. Louch. „Variable t-tubule organization and Ca2+ homeostasis across the atria“. American Journal of Physiology-Heart and Circulatory Physiology 307, Nr. 4 (15.08.2014): H609—H620. http://dx.doi.org/10.1152/ajpheart.00295.2014.
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Although t-tubules have traditionally been thought to be absent in atrial cardiomyocytes, recent studies have suggested that t-tubules exist in the atria of large mammals. However, it is unclear whether regional differences in t-tubule organization exist that define cardiomyocyte function across the atria. We sought to investigate regional t-tubule density in pig and rat atria and the consequences for cardiomyocyte Ca2+ homeostasis. We observed t-tubules in approximately one-third of rat atrial cardiomyocytes, in both tissue cryosections and isolated cardiomyocytes. In a minority (≈10%) of atrial cardiomyocytes, the t-tubular network was well organized, with a transverse structure resembling that of ventricular cardiomyocytes. In both rat and pig atrial tissue, we observed higher t-tubule density in the epicardium than in the endocardium. Consistent with high variability in the distribution of t-tubules and Ca2+ channels among cells, L-type Ca2+ current amplitude was also highly variable and steeply dependent on capacitance and t-tubule density. Accordingly, Ca2+ transients showed great variability in Ca2+ release synchrony. Simultaneous imaging of the cell membrane and Ca2+ transients confirmed t-tubule functionality. Results from mathematical modeling indicated that a transmural gradient in t-tubule organization and Ca2+ release kinetics supports synchronization of contraction across the atrial wall and may underlie transmural differences in the refractory period. In conclusion, our results indicate that t-tubule density is highly variable across the atria. We propose that higher t-tubule density in cells localized in the epicardium may promote synchronization of contraction across the atrial wall.
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Kong, Cherrie H. T., Eva A. Rog-Zielinska, Peter Kohl, Clive H. Orchard und Mark B. Cannell. „Solute movement in the t-tubule system of rabbit and mouse cardiomyocytes“. Proceedings of the National Academy of Sciences 115, Nr. 30 (10.07.2018): E7073—E7080. http://dx.doi.org/10.1073/pnas.1805979115.
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Cardiac transverse (t-) tubules carry both electrical excitation and solutes toward the cell center but their ability to transport small molecules is unclear. While fluorescence recovery after photobleaching (FRAP) can provide an approach to measure local solute movement, extraction of diffusion coefficients is confounded by cell and illumination beam geometries. In this study, we use measured cellular geometry and detailed computer modeling to derive the apparent diffusion coefficient of a 1-kDa solute inside the t-tubular system of rabbit and mouse ventricular cardiomyocytes. This approach shows that diffusion within individual t-tubules is more rapid than previously reported. T-tubule tortuosity, varicosities, and the presence of longitudinal elements combine to substantially reduce the apparent rate of solute movement. In steady state, large (>4 kDa) solutes did not freely fill the t-tubule lumen of both species and <50% of the t-tubule volume was available to solutes >70 kDa. Detailed model fitting of FRAP data suggests that solute diffusion is additionally restricted at the t-tubular entrance and this effect was larger in mouse than in rabbit. The possible structural basis of this effect was investigated using electron microscopy and tomography. Near the cell surface, mouse t-tubules are more tortuous and filled with an electron-dense ground substance, previously identified as glycocalyx and a polyanionic mesh. Solute movement in the t-tubule network of rabbit and mouse appears to be explained by their different geometric properties, which impacts the use of these species for understanding t-tubule function and the consequences of changes associated with t-tubule disease.
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Uchida, Keita, Azadeh Nikouee, Greta Tamkus und Anatoli N. Lopatin. „T-Tubular Constrictions Promote T-Tubule Sealing“. Biophysical Journal 114, Nr. 3 (Februar 2018): 619a. http://dx.doi.org/10.1016/j.bpj.2017.11.3349.
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Bryant, Simon M., Cherrie H. T. Kong, Judy J. Watson, Hanne C. Gadeberg, David M. Roth, Hemal H. Patel, Mark B. Cannell, Andrew F. James und Clive H. Orchard. „Caveolin-3 KO disrupts t-tubule structure and decreases t-tubular ICa density in mouse ventricular myocytes“. American Journal of Physiology-Heart and Circulatory Physiology 315, Nr. 5 (01.11.2018): H1101—H1111. http://dx.doi.org/10.1152/ajpheart.00209.2018.
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Caveolin-3 (Cav-3) is a protein that has been implicated in t-tubule formation and function in cardiac ventricular myocytes. In cardiac hypertrophy and failure, Cav-3 expression decreases, t-tubule structure is disrupted, and excitation-contraction coupling is impaired. However, the extent to which the decrease in Cav-3 expression underlies these changes is unclear. We therefore investigated the structure and function of myocytes isolated from the hearts of Cav-3 knockout (KO) mice. These mice showed cardiac dilatation and decreased ejection fraction in vivo compared with wild-type control mice. Isolated KO myocytes showed cellular hypertrophy, altered t-tubule structure, and decreased L-type Ca2+ channel current ( ICa) density. This decrease in density occurred predominantly in the t-tubules, with no change in total ICa, and was therefore a consequence of the increase in membrane area. Cav-3 KO had no effect on L-type Ca2+ channel expression, and C3SD peptide, which mimics the scaffolding domain of Cav-3, had no effect on ICa in KO myocytes. However, inhibition of PKA using H-89 decreased ICa at the surface and t-tubule membranes in both KO and wild-type myocytes. Cav-3 KO had no significant effect on Na+/Ca2+ exchanger current or Ca2+ release. These data suggest that Cav-3 KO causes cellular hypertrophy, thereby decreasing t-tubular ICa density. NEW & NOTEWORTHY Caveolin-3 (Cav-3) is a protein that inhibits hypertrophic pathways, has been implicated in the formation and function of cardiac t-tubules, and shows decreased expression in heart failure. This study demonstrates that Cav-3 knockout mice show cardiac dysfunction in vivo, while isolated ventricular myocytes show cellular hypertrophy, changes in t-tubule structure, and decreased t-tubular L-type Ca2+ current density, suggesting that decreased Cav-3 expression contributes to these changes in cardiac hypertrophy and failure.
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Hong, TingTing, und Robin M. Shaw. „Cardiac T-Tubule Microanatomy and Function“. Physiological Reviews 97, Nr. 1 (Januar 2017): 227–52. http://dx.doi.org/10.1152/physrev.00037.2015.
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Unique to striated muscle cells, transverse tubules (t-tubules) are membrane organelles that consist of sarcolemma penetrating into the myocyte interior, forming a highly branched and interconnected network. Mature t-tubule networks are found in mammalian ventricular cardiomyocytes, with the transverse components of t-tubules occurring near sarcomeric z-discs. Cardiac t-tubules contain membrane microdomains enriched with ion channels and signaling molecules. The microdomains serve as key signaling hubs in regulation of cardiomyocyte function. Dyad microdomains formed at the junctional contact between t-tubule membrane and neighboring sarcoplasmic reticulum are critical in calcium signaling and excitation-contraction coupling necessary for beat-to-beat heart contraction. In this review, we provide an overview of the current knowledge in gross morphology and structure, membrane and protein composition, and function of the cardiac t-tubule network. We also review in detail current knowledge on the formation of functional membrane subdomains within t-tubules, with a particular focus on the cardiac dyad microdomain. Lastly, we discuss the dynamic nature of t-tubules including membrane turnover, trafficking of transmembrane proteins, and the life cycles of membrane subdomains such as the cardiac BIN1-microdomain, as well as t-tubule remodeling and alteration in diseased hearts. Understanding cardiac t-tubule biology in normal and failing hearts is providing novel diagnostic and therapeutic opportunities to better treat patients with failing hearts.
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Uchida, Keita, Ian Moench, Greta Tamkus und Anatoli N. Lopatin. „Small membrane permeable molecules protect against osmotically induced sealing of t-tubules in mouse ventricular myocytes“. American Journal of Physiology-Heart and Circulatory Physiology 311, Nr. 1 (01.07.2016): H229—H238. http://dx.doi.org/10.1152/ajpheart.00836.2015.
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Cardiac t-tubules are critical for efficient excitation-contraction coupling but become significantly remodeled during various stress conditions. However, the mechanisms by which t-tubule remodeling occur are poorly understood. Recently, we demonstrated that recovery of mouse ventricular myocytes after hyposmotic shock is associated with t-tubule sealing. In this study, we found that the application of Small Membrane Permeable Molecules (SMPM) such as DMSO, formamide and acetamide upon washout of hyposmotic solution significantly reduced the amount of extracellular dextran trapped within sealed t-tubules. The SMPM protection displayed sharp biphasic concentration dependence that peaks at ∼140 mM leading to >3- to 4-fold reduction in dextran trapping. Consistent with these data, detailed analysis of the effects of DMSO showed that the magnitude of normalized inward rectifier tail current ( IK1,tail), an electrophysiological marker of t-tubular integrity, was increased ∼2-fold when hyposmotic stress was removed in the presence of 1% DMSO (∼140 mM). Analysis of dynamics of cardiomyocytes shrinking during resolution of hyposmotic stress revealed only minor increase in shrinking rate in the presence of 1% DMSO, and cell dimensions returned fully to prestress values in both control and DMSO groups. Application and withdrawal of 10% DMSO in the absence of preceding hyposmotic shock induced classical t-tubule sealing. This suggests that the biphasic concentration dependence originated from an increase in secondary t-tubule sealing when high SMPM concentrations are removed. Overall, the data suggest that SMPM protect against sealing of t-tubules following hyposmotic stress, likely through membrane modification and essentially independent of their osmotic effects.
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Orchard, Clive. „T-tubule trouble“. Journal of Physiology 574, Nr. 2 (06.07.2006): 330. http://dx.doi.org/10.1113/jphysiol.2006.113803.
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8
Chung, Ka Young, Misuk Kang und Jeffery W. Walker. „Contractile regulation by overexpressed ETArequires intact T tubules in adult rat ventricular myocytes“. American Journal of Physiology-Heart and Circulatory Physiology 294, Nr. 5 (Mai 2008): H2391—H2399. http://dx.doi.org/10.1152/ajpheart.00011.2008.
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Endothelin (ET)-1 regulates the contractility and growth of the heart by binding G protein-coupled receptors of the ET type A receptor (ETA)/ET type B (ETB) receptor family. ETA, the predominant ET-1 receptor subtype in myocardium, is thought to localize preferentially within cardiac T tubules, but the consequences of mislocalization are not fully understood. Here we examined the effects of the overexpression of ETAin conjunction with T-tubule loss in cultured adult rat ventricular myocytes. In adult myocytes cultured for 3 to 4 days, the normally robust positive inotropic effect (PIE) of ET-1 was lost in parallel with T-tubule degeneration and a decline in ETAprotein levels. In these T tubule-compromised myocytes, an overexpression of ETAusing an adenoviral vector did not rescue the responsiveness to ET-1, despite the robust expression in the surface sarcolemma. The inclusion of the actin polymerization inhibitor cytochalasin D (CD) during culture prevented gross morphological changes including a loss of T tubules and a rounding of intercalated discs, but CD alone did not rescue the responsiveness to ET-1 or prevent ETAdownregulation. The rescue of a normal PIE in 3- to 4-day cultured myocytes required both an increased expression of ETAand intact T tubules (preserved with CD). Therefore, the activation of ETAlocalized in T tubules was associated with a strong PIE, whereas the activation of ETAin surface sarcolemma was not. The results provide insight into the pathological cardiac conditions in which ETAis upregulated and T-tubule morphology is altered.
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Jayasinghe, Isuru D., Alexander H. Clowsley, Michelle Munro, Yufeng Hou, David J. Crossman und Christian Soeller. „Revealing t-tubules in striated muscle with new optical super-resolution microscopy techniques“. European Journal of Translational Myology 25, Nr. 1 (24.12.2014): 15. http://dx.doi.org/10.4081/ejtm.2015.4747.
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The t-tubular system plays a central role in the synchronisation of calcium signalling and excitation-contraction coupling in most striated muscle cells. Light microscopy has been used for imaging t-tubules for well over 100 years and together with electron microscopy (EM), has revealed the three-dimensional complexities of the t-system topology within cardiomyocytes and skeletal muscle fibres from a range of species. The emerging super-resolution single molecule localisation microscopy (SMLM) techniques are offering a near 10-fold improvement over the resolution of conventional fluorescence light microscopy methods, with the ability to spectrally resolve nanometre scale distributions of multiple molecular targets. In conjunction with the next generation of electron microscopy, SMLM has allowed the visualisation and quantification of intricate t-tubule morphologies within large areas of muscle cells at an unprecedented level of detail. In this paper, we review recent advancements in the t-tubule structural biology with the utility of various microscopy techniques. We outline the technical considerations in adapting SMLM to study t-tubules and its potential to further our understanding of the molecular processes that underlie the sub-micron scale structural alterations observed in a range of muscle pathologies.
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Muñoz, P., M. Rosemblatt, X. Testar, M. Palacín, G. Thoidis, P. F. Pilch und A. Zorzano. „The T-tubule is a cell-surface target for insulin-regulated recycling of membrane proteins in skeletal muscle“. Biochemical Journal 312, Nr. 2 (01.12.1995): 393–400. http://dx.doi.org/10.1042/bj3120393.
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(1) In this study we have determined the distribution of various membrane proteins involved in insulin-activated glucose transport in T-tubules and in sarcolemma from rat skeletal muscle. Two independent experimental approaches were used to determine the presence of membrane proteins in T-tubules: (i) the purification of T-tubules free from sarcolemmal membranes by lectin agglutination, and (ii) T-tubule vesicle immunoadsorption. These methods confirmed that T-tubules from rat skeletal muscle were enriched with dihydropyridine receptors and tt28 protein and did not contain the sarcolemmal markers dystrophin or beta 1-integrin. Both types of experiments revealed an abundant content of GLUT4 glucose carriers, insulin receptors and SCAMPs (secretory carrier membrane proteins) in T-tubule membranes. (2) Acute administration in vivo of insulin caused an increased abundance of GLUT4 in T-tubules and sarcolemma. On the contrary, insulin led to a 50% reduction in insulin receptors present in T-tubules and in sarcolemma, demonstrating that insulin-induced insulin receptor internalization affects T-tubules in the muscle fibre. The alteration in the content of GLUT4 and insulin receptors in T-tubules was a consequence of insulin-induced redistribution of these proteins. SCAMPs also redistributed in muscle membranes in response to insulin. They were recruited by insulin from intracellular high-density fractions to intracellular lighter-density fractions and to the cell surface, showing a pattern of insulin-induced cellular redistribution distinct from those of GLUT4 and the insulin receptor. (3) In conclusion, the T-tubule is a cell-surface target for membrane proteins involved in recycling such as SCAMPs or for membrane proteins that acutely redistribute in response to insulin such as GLUT4 or insulin receptors.
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Zhou, Jingsong, Jianxun Yi, Leandro Royer, Bradley S. Launikonis, Adom González, Jesús García und Eduardo Ríos. „A probable role of dihydropyridine receptors in repression of Ca2+ sparks demonstrated in cultured mammalian muscle“. American Journal of Physiology-Cell Physiology 290, Nr. 2 (Februar 2006): C539—C553. http://dx.doi.org/10.1152/ajpcell.00592.2004.
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To activate skeletal muscle contraction, action potentials must be sensed by dihydropyridine receptors (DHPRs) in the T tubule, which signal the Ca2+ release channels or ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR) to open. We demonstrate here an inhibitory effect of the T tubule on the production of sparks of Ca2+ release. Murine primary cultures were confocally imaged for Ca2+ detection and T tubule visualization. After 72 h of differentiation, T tubules extended from the periphery for less than one-third of the myotube radius. Spontaneous Ca2+ sparks were found away from the region of cells where tubules were found. Immunostaining showed RyR1 and RyR3 isoforms in all areas, implying inhibition of both isoforms by a T tubule component. To test for a role of DHPRs in this inhibition, we imaged myotubes from dysgenic mice ( mdg) that lack DHPRs. These exhibited T tubule development similar to that of normal myotubes, but produced few sparks, even in regions where tubules were absent. To increase spark frequency, a high-Ca2+ saline with 1 mM caffeine was used. Wild-type cells in this saline plus 50 μM nifedipine retained the topographic suppression pattern of sparks, but dysgenic cells in high-Ca2+ saline did not. Shifted excitation and emission ratios of indo-1 in the cytosol or mag-indo-1 in the SR were used to image [Ca2+] in these compartments. Under the conditions of interest, wild-type and mdg cells had similar levels of free [Ca2+] in cytosol and SR. These data suggest that DHPRs play a critical role in reducing the rate of spontaneous opening of Ca2+ release channels and/or their susceptibility to Ca2+-induced activation, thereby suppressing the production of Ca2+ sparks.
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Gross, Polina, Jaslyn Johnson, Carlos M. Romero, Deborah M. Eaton, Claire Poulet, Jose Sanchez-Alonso, Carla Lucarelli et al. „Interaction of the Joining Region in Junctophilin-2 With the L-Type Ca 2+ Channel Is Pivotal for Cardiac Dyad Assembly and Intracellular Ca 2+ Dynamics“. Circulation Research 128, Nr. 1 (08.01.2021): 92–114. http://dx.doi.org/10.1161/circresaha.119.315715.
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Rationale: Ca 2+ -induced Ca 2+ release (CICR) in normal hearts requires close approximation of L-type calcium channels (LTCCs) within the transverse tubules (T-tubules) and RyR (ryanodine receptors) within the junctional sarcoplasmic reticulum. CICR is disrupted in cardiac hypertrophy and heart failure, which is associated with loss of T-tubules and disruption of cardiac dyads. In these conditions, LTCCs are redistributed from the T-tubules to disrupt CICR. The molecular mechanism responsible for LTCCs recruitment to and from the T-tubules is not well known. JPH (junctophilin) 2 enables close association between T-tubules and the junctional sarcoplasmic reticulum to ensure efficient CICR. JPH2 has a so-called joining region that is located near domains that interact with T-tubular plasma membrane, where LTCCs are housed. The idea that this joining region directly interacts with LTCCs and contributes to LTCC recruitment to T-tubules is unknown. Objective: To determine if the joining region in JPH2 recruits LTCCs to T-tubules through direct molecular interaction in cardiomyocytes to enable efficient CICR. Methods and Results: Modified abundance of JPH2 and redistribution of LTCC were studied in left ventricular hypertrophy in vivo and in cultured adult feline and rat ventricular myocytes. Protein-protein interaction studies showed that the joining region in JPH2 interacts with LTCC-α1C subunit and causes LTCCs distribution to the dyads, where they colocalize with RyRs. A JPH2 with induced mutations in the joining region (mut PG1 JPH2) caused T-tubule remodeling and dyad loss, showing that an interaction between LTCC and JPH2 is crucial for T-tubule stabilization. mut PG1 JPH2 caused asynchronous Ca 2+ -release with impaired excitation-contraction coupling after β-adrenergic stimulation. The disturbed Ca 2+ regulation in mut PG1 JPH2 overexpressing myocytes caused calcium/calmodulin-dependent kinase II activation and altered myocyte bioenergetics. Conclusions: The interaction between LTCC and the joining region in JPH2 facilitates dyad assembly and maintains normal CICR in cardiomyocytes.
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Louch, William E., Ole M. Sejersted und Fredrik Swift. „There Goes the Neighborhood: Pathological Alterations in T-Tubule Morphology and Consequences for Cardiomyocyte Handling“. Journal of Biomedicine and Biotechnology 2010 (2010): 1–17. http://dx.doi.org/10.1155/2010/503906.
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T-tubules are invaginations of the cardiomyocyte membrane into the cell interior which form a tortuous network. T-tubules provide proximity between the electrically excitable cell membrane and the sarcoplasmic reticulum, the main intracellular store. Tight coupling between the rapidly spreading action potential and release units in the SR membrane ensures synchronous release throughout the cardiomyocyte. This is a requirement for rapid and powerful contraction. In recent years, it has become clear that T-tubule structure and composition are altered in several pathological states which may importantly contribute to contractile defects in these conditions. In this review, we describe the “neighborhood” of proteins in the dyadic cleft which locally controls cardiomyocyte homeostasis and how alterations in T-tubule structure and composition may alter this neighborhood during heart failure, atrial fibrillation, and diabetic cardiomyopathy. Based on this evidence, we propose that T-tubules have the potential to serve as novel therapeutic targets.
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Yamakawa, Sean, Daniel Wu, Mona Dasgupta, Havisha Pedamallu, Binita Gupta, Rishi Modi, Maryam Mufti et al. „Role of t-tubule remodeling on mechanisms of abnormal calcium release during heart failure development in canine ventricle“. American Journal of Physiology-Heart and Circulatory Physiology 320, Nr. 4 (01.04.2021): H1658—H1669. http://dx.doi.org/10.1152/ajpheart.00946.2020.
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Three-dimensional analysis of t-tubule density showed t-tubule disruption throughout the whole myocyte in failing dog ventricle. A double-linear relationship between Ca2+ release and t-tubule density displays a steeper slope at t-tubule densities below a threshold value (∼1.5%) above which there is little effect on Ca2+ release (T-tubule reserve). T-tubule loss increases incidence of triggered Ca2+ waves. Chemically induced t-tubule disruption suggests that t-tubule loss alone is a critical component of abnormal Ca2+ cycling in heart failure.
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Dibb, Katharine M., William E. Louch und Andrew W. Trafford. „Cardiac Transverse Tubules in Physiology and Heart Failure“. Annual Review of Physiology 84, Nr. 1 (10.02.2022): 229–55. http://dx.doi.org/10.1146/annurev-physiol-061121-040148.
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In mammalian cardiac myocytes, the plasma membrane includes the surface sarcolemma but also a network of membrane invaginations called transverse (t-) tubules. These structures carry the action potential deep into the cell interior, allowing efficient triggering of Ca2+ release and initiation of contraction. Once thought to serve as rather static enablers of excitation-contraction coupling, recent work has provided a newfound appreciation of the plasticity of the t-tubule network's structure and function. Indeed, t-tubules are now understood to support dynamic regulation of the heartbeat across a range of timescales, during all stages of life, in both health and disease. This review article aims to summarize these concepts, with consideration given to emerging t-tubule regulators and their targeting in future therapies.
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Muñoz, P., M. Rosemblatt, X. Testar, M. Palacín und A. Zorzano. „Isolation and characterization of distinct domains of sarcolemma and T-tubules from rat skeletal muscle“. Biochemical Journal 307, Nr. 1 (01.04.1995): 273–80. http://dx.doi.org/10.1042/bj3070273.
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1. Several cell-surface domains of sarcolemma and T-tubule from skeletal-muscle fibre were isolated and characterized. 2. A protocol of subcellular fractionation was set up that involved the sequential low- and high-speed homogenization of rat skeletal muscle followed by KCl washing, Ca2+ loading and sucrose-density-gradient centrifugation. This protocol led to the separation of cell-surface membranes from membranes enriched in sarcoplasmic reticulum and intracellular GLUT4-containing vesicles. 3. Agglutination of cell-surface membranes using wheat-germ agglutinin allowed the isolation of three distinct cell-surface membrane domains: sarcolemmal fraction 1 (SM1), sarcolemmal fraction 2 (SM2) and a T-tubule fraction enriched in protein tt28 and the alpha 2-component of dihydropyridine receptor. 4. Fractions SM1 and SM2 represented distinct sarcolemmal subcompartments based on different compositions of biochemical markers: SM2 was characterized by high levels of beta 1-integrin and dystrophin, and SM1 was enriched in beta 1-integrin but lacked dystrophin. 5. The caveolae-associated molecule caveolin was very abundant in SM1, SM2 and T-tubules, suggesting the presence of caveolae or caveolin-rich domains in these cell-surface membrane domains. In contrast, clathrin heavy chain was abundant in SM1 and T-tubules, but only trace levels were detected in SM2. 6. Immunoadsorption of T-tubule vesicles with antibodies against protein tt28 and against GLUT4 revealed the presence of GLUT4 in T-tubules under basal conditions and it also allowed the identification of two distinct pools of T-tubules showing different contents of tt28 and dihydropyridine receptors. 7. Our data on distribution of clathrin and dystrophin reveal the existence of subcompartments in sarcolemma from muscle fibre, featuring selective mutually exclusive components. T-tubules contain caveolin and clathrin suggesting that they contain caveolin- and clathrin-rich domains. Furthermore, evidence for the heterogeneous distribution of membrane proteins in T-tubules is also presented.
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Martone, M. E., V. M. Edelman, A. Thor, S. J. Young, S. P. Lamont, J. Ross und M. H. Ellisman. „Three-Dimensional Analysis of Tranverse Tubules in Normal and Failing Heart: A Combined Confocal and High Voltage Electron Microscope Study“. Microscopy and Microanalysis 3, S2 (August 1997): 231–32. http://dx.doi.org/10.1017/s1431927600008047.
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Early electron microscopic studies documented that significant changes in the membrane systems of cardiac cells occur in both ischemic and non-ischemic heart failure. These studies relied on analysis of two-dimensional sections and although quantitative changes were observed, the overall organization of the tranverse tubules (T-tubules) and the sarcoplasmic reticulum could not be assessed. In a 3-dimensional study using high voltage electron microscopy (EM) of the T-tubules in spontaneously hypertensive rats, Nakamura and Hama (1991) observed that concomitant with an increase in surface area, the T-tubule system becomes progressively more disorganized and exhibits structural irregularities such as increased numbers of longitudinal tubules, numerous short dead end branches and complex tubular aggregates. These authors suggested that this disorganization may interfere with synchronous contraction over the entire cell.In the present study, we examined the 3-dimensional organization of T-tubules in the left ventricle of explanted human hearts using confocal microscopy and EM tomography.
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Safi, Frozan, Alina Shteiman-Kotler, Yunan Zhong, Konstantin G. Iliadi, Gabrielle L. Boulianne und Daniela Rotin. „Drosophila Nedd4-long reduces Amphiphysin levels in muscles and leads to impaired T-tubule formation“. Molecular Biology of the Cell 27, Nr. 6 (15.03.2016): 907–18. http://dx.doi.org/10.1091/mbc.e15-06-0420.
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Drosophila Nedd4 (dNedd4) is a HECT ubiquitin ligase with two main splice isoforms: dNedd4-short (dNedd4S) and -long (dNedd4Lo). DNedd4Lo has a unique N-terminus containing a Pro-rich region. We previously showed that whereas dNedd4S promotes neuromuscular synaptogenesis, dNedd4Lo inhibits it and impairs larval locomotion. To delineate the cause of the impaired locomotion, we searched for binding partners to the N-terminal unique region of dNedd4Lo in larval lysates using mass spectrometry and identified Amphiphysin (dAmph). dAmph is a postsynaptic protein containing SH3-BAR domains and regulates muscle transverse tubule (T-tubule) formation in flies. We validated the interaction by coimmunoprecipitation and showed direct binding between dAmph-SH3 domain and dNedd4Lo N-terminus. Accordingly, dNedd4Lo was colocalized with dAmph postsynaptically and at muscle T-tubules. Moreover, expression of dNedd4Lo in muscle during embryonic development led to disappearance of dAmph and impaired T-tubule formation, phenocopying amph-null mutants. This effect was not seen in muscles expressing dNedd4S or a catalytically-inactive dNedd4Lo(C→A). We propose that dNedd4Lo destabilizes dAmph in muscles, leading to impaired T-tubule formation and muscle function.
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Ibrahim, Michael, Julia Gorelik, Magdi H. Yacoub und Cesare M. Terracciano. „The structure and function of cardiac t-tubules in health and disease“. Proceedings of the Royal Society B: Biological Sciences 278, Nr. 1719 (22.06.2011): 2714–23. http://dx.doi.org/10.1098/rspb.2011.0624.
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The transverse tubules (t-tubules) are invaginations of the cell membrane rich in several ion channels and other proteins devoted to the critical task of excitation–contraction coupling in cardiac muscle cells (cardiomyocytes). They are thought to promote the synchronous activation of the whole depth of the cell despite the fact that the signal to contract is relayed across the external membrane. However, recent work has shown that t-tubule structure and function are complex and tightly regulated in healthy cardiomyocytes. In this review, we outline the rapidly accumulating knowledge of its novel roles and discuss the emerging evidence of t-tubule dysfunction in cardiac disease, especially heart failure. Controversy surrounds the t-tubules' regulatory elements, and we draw attention to work that is defining these elements from the genetic and the physiological levels. More generally, this field illustrates the challenges in the dissection of the complex relationship between cellular structure and function.
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Flucher, B. E., J. L. Phillips und J. A. Powell. „Dihydropyridine receptor alpha subunits in normal and dysgenic muscle in vitro: expression of alpha 1 is required for proper targeting and distribution of alpha 2.“ Journal of Cell Biology 115, Nr. 5 (01.12.1991): 1345–56. http://dx.doi.org/10.1083/jcb.115.5.1345.
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We have studied the subcellular distribution of the alpha 1 and alpha 2 subunits of the skeletal muscle dihydropyridine (DHP) receptor with immunofluorescence labeling of normal and dysgenic (mdg) muscle in culture. In normal myotubes both alpha subunits were localized in clusters associated with the T-tubule membranes of longitudinally as well as transversely oriented T-tubules. The DHP receptor-rich domains may represent the sites where triad junctions with the sarcoplasmic reticulum are being formed. In cultures from dysgenic muscle the alpha 1 subunit was undetectable and the distribution patterns of the alpha 2 subunit were abnormal. The alpha subunit did not form clusters nor was it discretely localized in the T-tubule system. Instead, alpha 2 was found diffusely distributed in parts of the T-system, in structures in the perinuclear region and in the plasma membrane. These results suggest that an interaction between the two alpha subunits is required for the normal distribution of the alpha 2 subunit in the T-tubule membranes. Spontaneous fusion of normal non-muscle cells with dysgenic myotubes resulted in a regional expression of the alpha 1 polypeptide near the foreign nuclei, thus defining the nuclear domain of a T-tubule membrane protein in multi-nucleated muscle cells. Furthermore, the normal intracellular distribution of the alpha 2 polypeptide was restored in domains containing a foreign "rescue" nucleus; this supports the idea that direct interactions between the DHP receptor alpha 1 and alpha 2 subunits are involved in the organization of the junctional T-tubule membranes.
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Fujise, Kenshiro, Satoru Noguchi und Tetsuya Takeda. „Centronuclear Myopathy Caused by Defective Membrane Remodelling of Dynamin 2 and BIN1 Variants“. International Journal of Molecular Sciences 23, Nr. 11 (03.06.2022): 6274. http://dx.doi.org/10.3390/ijms23116274.
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Centronuclear myopathy (CNM) is a congenital myopathy characterised by centralised nuclei in skeletal myofibers. T-tubules, sarcolemmal invaginations required for excitation-contraction coupling, are disorganised in the skeletal muscles of CNM patients. Previous studies showed that various endocytic proteins are involved in T-tubule biogenesis and their dysfunction is tightly associated with CNM pathogenesis. DNM2 and BIN1 are two causative genes for CNM that encode essential membrane remodelling proteins in endocytosis, dynamin 2 and BIN1, respectively. In this review, we overview the functions of dynamin 2 and BIN1 in T-tubule biogenesis and discuss how their dysfunction in membrane remodelling leads to CNM pathogenesis.
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Richards, M. A., J. D. Clarke, P. Saravanan, N. Voigt, D. Dobrev, D. A. Eisner, A. W. Trafford und K. M. Dibb. „Transverse tubules are a common feature in large mammalian atrial myocytes including human“. American Journal of Physiology-Heart and Circulatory Physiology 301, Nr. 5 (November 2011): H1996—H2005. http://dx.doi.org/10.1152/ajpheart.00284.2011.
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Transverse (t) tubules are surface membrane invaginations that are present in all mammalian cardiac ventricular cells. The apposition of L-type Ca2+ channels on t tubules with the sarcoplasmic reticulum (SR) constitutes a “calcium release unit” and allows close coupling of excitation to the rise in systolic Ca2+. T tubules are virtually absent in the atria of small mammals, and therefore Ca2+ release from the SR occurs initially at the periphery of the cell and then propagates into the interior. Recent work has, however, shown the occurrence of t tubules in atrial myocytes from sheep. As in the ventricle, Ca2+ release in these cells occurs simultaneously in central and peripheral regions. T tubules in both the atria and the ventricle are lost in disease, contributing to cellular dysfunction. The aim of this study was to determine if the occurrence of t tubules in the atrium is restricted to sheep or is a more general property of larger mammals including humans. In atrial tissue sections from human, horse, cow, and sheep, membranes were labeled using wheat germ agglutinin. As previously shown in sheep, extensive t-tubule networks were present in horse, cow, and human atrial myocytes. Analysis shows half the volume of the cell lies within 0.64 ± 0.03, 0.77 ± 0.03, 0.84 ± 0.03, and 1.56 ± 0.19 μm of t-tubule membrane in horse, cow, sheep, and human atrial myocytes, respectively. The presence of t tubules in the human atria may play an important role in determining the spatio-temporal properties of the systolic Ca2+ transient and how this is perturbed in disease.
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Chen, F., G. Mottino, T. S. Klitzner, K. D. Philipson und J. S. Frank. „Distribution of the Na+/Ca2+ exchange protein in developing rabbit myocytes“. American Journal of Physiology-Cell Physiology 268, Nr. 5 (01.05.1995): C1126—C1132. http://dx.doi.org/10.1152/ajpcell.1995.268.5.c1126.
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The Na+/Ca2+ exchanger is a major pathway for transmembrane flux of Ca2+ in cardiac cells. Immunolabeling in adult rabbit myocytes showed localization of the Na+/Ca2+ exchanger to the peripheral sarcolemma and especially in the T tubules. Previous studies have also demonstrated higher Na+/Ca2+ exchanger activity in fetal and newborn rabbit hearts in which the T tubular system is not completely developed. Indirect immunofluorescent studies were performed to localize the Na+/Ca2+ exchanger in isolated myocytes from immature (5, 11, 17, and 30 days) and adult rabbits. Cells were incubated with a monoclonal antibody to the exchanger followed by fluorescein-labeled goat anti-mouse antibody. It is found that at 5 days of age the immunofluorescent labeling was very intense and confined to the peripheral sarcolemma. After 11 days of age, localization of labeling followed the development of the T tubules. The exchanger appeared in the T tubules as soon as they were formed. The Na+/Ca2+ exchange protein is abundantly localized to the peripheral sarcolemma before and during the development of T tubule system.
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Pasqualin, Côme, François Gannier, Claire O. Malécot, Pierre Bredeloux und Véronique Maupoil. „Automatic quantitative analysis of t-tubule organization in cardiac myocytes using ImageJ“. American Journal of Physiology-Cell Physiology 308, Nr. 3 (01.02.2015): C237—C245. http://dx.doi.org/10.1152/ajpcell.00259.2014.
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The transverse tubule system in mammalian striated muscle is highly organized and contributes to optimal and homogeneous contraction. Diverse pathologies such as heart failure and atrial fibrillation include disorganization of t-tubules and contractile dysfunction. Few tools are available for the quantification of the organization of the t-tubule system. We developed a plugin for the ImageJ/Fiji image analysis platform developed by the National Institutes of Health. This plugin (TTorg) analyzes raw confocal microscopy images. Analysis options include the whole image, specific regions of the image (cropping), and z-axis analysis of the same image. Batch analysis of a series of images with identical criteria is also one of the options. There is no need to either reorientate any specimen to the horizontal or to do a thresholding of the image to perform analysis. TTorg includes a synthetic “myocyte-like” image generator to test the plugin's efficiency in the user's own experimental conditions. This plugin was validated on synthetic images for different simulated cell characteristics and acquisition parameters. TTorg was able to detect significant differences between the organization of the t-tubule systems in experimental data of mouse ventricular myocytes isolated from wild-type and dystrophin-deficient mice. TTorg is freely distributed, and its source code is available. It provides a reliable, easy-to-use, automatic, and unbiased measurement of t-tubule organization in a wide variety of experimental conditions.
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Flucher, B. E., S. B. Andrews und M. P. Daniels. „Molecular organization of transverse tubule/sarcoplasmic reticulum junctions during development of excitation-contraction coupling in skeletal muscle.“ Molecular Biology of the Cell 5, Nr. 10 (Oktober 1994): 1105–18. http://dx.doi.org/10.1091/mbc.5.10.1105.
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The relationship between the molecular composition and organization of the triad junction and the development of excitation-contraction (E-C) coupling was investigated in cultured skeletal muscle. Action potential-induced calcium transients develop concomitantly with the first expression of the dihydropyridine receptor (DHPR) and the ryanodine receptor (RyR), which are colocalized in clusters from the time of their earliest appearance. These DHPR/RyR clusters correspond to junctional domains of the transverse tubules (T-tubules) and sarcoplasmic reticulum (SR), respectively. Thus, at first contact T-tubules and SR form molecularly and structurally specialized membrane domains that support E-C coupling. The earliest T-tubule/SR junctions show structural characteristics of mature triads but are diverse in conformation and typically are formed before the extensive development of myofibrils. Whereas the initial formation of T-tubule/SR junctions is independent of association with myofibrils, the reorganization into proper triads occurs as junctions become associated with the border between the A band and the I band of the sarcomere. This final step in triad formation manifests itself in an increased density and uniformity of junctions in the cytoplasm, which in turn results in increased calcium release and reuptake rates.
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el-Hayek, R., M. Yano, B. Antoniu, J. R. Mickelson, C. F. Louis und N. Ikemoto. „Altered E-C coupling in triads isolated from malignant hyperthermia-susceptible porcine muscle“. American Journal of Physiology-Cell Physiology 268, Nr. 6 (01.06.1995): C1381—C1386. http://dx.doi.org/10.1152/ajpcell.1995.268.6.c1381.
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Triad vesicles were isolated from normal (N) and homozygous malignant hyperthermia-susceptible (MHS) porcine skeletal muscle, and two types of sarcoplasmic reticulum Ca2+ release were investigated: 1) polylysine-induced Ca2+ release (direct stimulation of the junctional foot protein), and 2) depolarization-induced Ca2+ release (stimulation of the junctional foot protein via the dihydropyridine receptor). At submaximal concentrations of polylysine, the rates of induced Ca2+ release from the MHS triads were greater than from normal triads. The T tubules of polarized triads were depolarized by the K(+)-to-Na+ ionic replacement protocol. Higher grades of T-tubule depolarization resulted in higher rates of Ca2+ release from both MHS and normal triads but, when compared at a given grade of T-tubule depolarization, the release rate was always greater from the MHS than from normal triads. Thus the activity of the SR Ca2+ release channel is always higher in MHS than in normal muscle at a given submaximal dose of release trigger. This difference is observed when the channel is stimulated directly by polylysine or indirectly via a depolarization-induced activation of the T-tubule dihydropyridine receptor.
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Carozzi, Amanda J., Elina Ikonen, Margaret R. Lindsay und Robert G. Parton. „Role of Cholesterol in Developing T-Tubules: Analogous Mechanisms for T-Tubule and Caveolae Biogenesis“. Traffic 1, Nr. 4 (April 2000): 326–41. http://dx.doi.org/10.1034/j.1600-0854.2000.010406.x.
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Brette, Fabien, und Clive Orchard. „Resurgence of Cardiac T-Tubule Research“. Physiology 22, Nr. 3 (Juni 2007): 167–73. http://dx.doi.org/10.1152/physiol.00005.2007.
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The transverse tubules of mammalian cardiac ventricular myocytes are invaginations of the surface membrane. Recent data have revealed that their structure and function are more complex than previously believed. Here, we review current knowledge about their role in cardiac function, focusing on Ca2+ signaling and changes observed in pathological conditions.
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Fu, Ying, und TingTing Hong. „BIN1 regulates dynamic t-tubule membrane“. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1863, Nr. 7 (Juli 2016): 1839–47. http://dx.doi.org/10.1016/j.bbamcr.2015.11.004.
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Crossman, David J., Alistair A. Young, Peter N. Ruygrok, Guy P. Nason, David Baddelely, Christian Soeller und Mark B. Cannell. „t-tubule disease: Relationship between t-tubule organization and regional contractile performance in human dilated cardiomyopathy“. Journal of Molecular and Cellular Cardiology 84 (Juli 2015): 170–78. http://dx.doi.org/10.1016/j.yjmcc.2015.04.022.
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Dombrowski, L., D. Roy, B. Marcotte und A. Marette. „A new procedure for the isolation of plasma membranes, T tubules, and internal membranes from skeletal muscle“. American Journal of Physiology-Endocrinology and Metabolism 270, Nr. 4 (01.04.1996): E667—E676. http://dx.doi.org/10.1152/ajpendo.1996.270.4.e667.
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A new subcellular fractionation procedure for the simultaneous isolation of plasma membranes and transverse (T) tubule membranes from a rat skeletal muscle was developed. This new technique allows the isolation and separation of plasma membranes and T tubules in distinct subcellular fractions, as revealed by the membrane distribution of enzymatic and immunologic markers of both cell surface compartments. The procedure also yields a novel membrane fraction that is devoid of markers of both surface domains but is markedly enriched with GLUT-4 glucose transporters, thus strongly suggesting that it represents an intracellular pool of GLUT-4. Using this new procedure, we found that acute in vivo insulin administration (30 min) increased GLUT-4 protein content in the plasma membrane and a T tubule fraction (by approximately 80%), whereas a smaller elevation (35%) was observed in another fraction enriched with T tubules. Insulin induced a concomitant reduction (approximately 40%) in GLUT-4 abundance in the intracellular fraction. These results further support the hypothesis that T tubules are involved in the regulation of glucose transport in skeletal muscle. This novel fractionation method will be useful in investigating the regulation of muscle GLUT-4 transporters in other physiological and disease states such as diabetes, where defective translocation of the transporter protein to either one or both cell surface domains is suspected to occur.
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Lauritzen, Hans P. M. M. „In vivo imaging of GLUT4 translocationThis paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.“ Applied Physiology, Nutrition, and Metabolism 34, Nr. 3 (Juni 2009): 420–23. http://dx.doi.org/10.1139/h09-043.
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In skeletal muscle, both insulin and muscle contractions mediate translocation of glucose transporter GLUT4 to the plasma membrane proper, the sarcolemma, and the specialized membrane channel network, the transverse (t)-tubules. Despite the fact that skeletal muscle glucose uptake plays a major role in normal conditions, in insulin resistance, and type II diabetes, the details of GLUT4 translocation and the intracellular signalling involved have not been fully described. A main reason is that the majority of experiments have been carried out in muscle cultures in vitro. In vitro cultured muscle is not fully differentiated and, therefore, diverges from real muscle, in that it has lower expression of GLUT4, an underdeveloped or nonexistent t-tubule network, and a reduced or nonexistent response to insulin. Thus, experiments carried out in cultured muscle cell systems might give misleading results on how GLUT4 translocation and the signalling involved takes place. To address this problem, a confocal imaging technique has been developed that allows delineation of the spartial and spatial distribution of GFP-tagged GLUT4 (GLUT4-GFP) translocation in living muscle fibers in situ in anesthetized mice. The effects of stimuli with insulin or in situ muscle contractions in fully differentiated muscle fibers can now be studied before, during, and after applying stimuli. Initial analysis of insulin-stimulated GLUT4-GFP translocation showed a delay in maximal translocation between the sarcolemma and t-tubules. Corresponding to the delay, we found that fluorescent tagged insulin reaches the sarcolemma first and then, with a delay, diffuses into the t-tubule system, enabling interaction with local insulin receptors and, in turn, triggering local insulin signalling and local GLUT4 translocation. In parallel, we showed that the majority of GLUT4 depot vesicles do not move long distances but are depleted locally in the sarcolemma or t-tubule regions. Analysis of GLUT4 translocation in insulin-resistant muscle showed that, primarily, GLUT4 recruitment in the t-tubule region is affected. We have now analysed the kinetics of contraction-mediated GLUT4 translocation and reinternalization, as well as dilineated some of the key signalling points involved in these processes.
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Zhang, Caimei, Biyi Chen, Yihui Wang, Ang Guo, Yiqun Tang, Tahsin Khataei, Yun Shi et al. „MG53 is dispensable for T-tubule maturation but critical for maintaining T-tubule integrity following cardiac stress“. Journal of Molecular and Cellular Cardiology 112 (November 2017): 123–30. http://dx.doi.org/10.1016/j.yjmcc.2017.08.007.
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Toutant, M., J. Barhanin, J. Bockaert und B. Rouot. „G-proteins in skeletal muscle. Evidence for a 40 kDa pertussis-toxin substrate in purified transverse tubules“. Biochemical Journal 254, Nr. 2 (01.09.1988): 405–9. http://dx.doi.org/10.1042/bj2540405.
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In muscle, it has been established that guanosine 5′-[gamma-thio]triphosphate (GTP[S]), a non-hydrolysable GTP analogue, elicits a rise in tension in chemically skinned fibres, and that pretreatment with Bordetella pertussis toxin (PTX) decreases GTP[S]-induced tension development [Di Virgilio, Salviati, Pozzan & Volpe (1986) EMBO J. 5, 259-262]. In the present study, G-proteins were analysed by PTX-catalysed ADP-ribosylation and by immunoblotting experiments at cellular and subcellular levels. First, the nature of the G-proteins present in neural and aneural zones of rat diaphragm muscle was investigated. PTX, known to catalyse the ADP-ribosylation of the alpha subunit of several G-proteins, was used to detect G-proteins. Three sequential extractions (low-salt-soluble, detergent-soluble and high-salt-soluble) were performed, and PTX was found to label two substrates of 41 and 40 kDa only in the detergent-soluble fraction. The addition of pure beta gamma subunits of G-proteins to the low-salt-soluble extract did not provide a way to detect PTX-catalysed ADP-ribosylation of G-protein alpha subunits in this hydrophilic fraction. In neural as well as in aneural zones, the 39 kDa PTX substrate, very abundant in the nervous system (Go alpha), was not observed. We then studied the nature of the G alpha subunits present in membranes from transverse tubules (T-tubules) purified from rabbit skeletal muscle. Only one 40 kDa PTX substrate was found in T-tubules, known to be the key element of excitation-contraction coupling. The presence of a G-protein in T-tubule membranes was further confirmed by the immunoreactivity detected with an anti-beta-subunit antiserum. A 40 kDa protein was also detected in T-tubule membranes with an antiserum raised against a purified bovine brain Go alpha. The presence of two PTX substrates (41 and 40 kDa) in equal amounts in total muscle extracts, compared with only one (40 kDa) found in purified T-tubule membranes, suggests that this 40 kDa PTX substrate might be involved in excitation-contraction coupling.
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Marsigliante, S., A. Muscella, S. Barker und C. Storelli. „Angiotensin II modulates the activity of the Na+/K+ATPase in eel kidney“. Journal of Endocrinology 165, Nr. 1 (01.04.2000): 147–56. http://dx.doi.org/10.1677/joe.0.1650147.
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We have previously shown that angiotensin II (Ang II) has a role at the level of the eel gill chloride cell regulating sodium balance, and therefore osmoregulation; the purpose of the present study was to extend these findings to another important osmoregulatory organ, the kidney. By catalytic histochemistry Na(+)/K(+)ATPase activity was found in both sea water (SW)- and freshwater (FW)-adapted eel kidney, particularly at the level of both proximal and distal tubules. Quantitation of tubular cell Na(+)/K(+)ATPase activity, by imaging, gave values in SW-adapted eels which were double those found in FW-adapted eels (Student's t-test: P<0.0001). This was due to a reduced number of positive tubules present in FW-adapted eels compared with SW-adapted eels. By conventional enzymatic assay, the Na(+)/K(+)ATPase activity in isolated tubular cells from SW-adapted eels showed values 1.85-fold higher those found in FW-adapted eels (Student's ttest: P<0.0001). Perfusion of kidney for 20 min with 100 nM Ang II provoked a significant increase (1.8-fold) in Na(+)/K(+)ATPase activity in FW, due to up-regulation of Na(+)/K(+)ATPase activity in a significantly larger number of tubules (Student's t-test: P<0.0001). The effect of 100 nM Ang II in SW-adapted kidneys was not significant. Stimulation with increasing Ang II concentrations was performed on isolated kidney tubule cells: Ang II provoked a dose-dependent stimulation of the Na(+)/K(+)ATPase activity in FW-adapted eels, reaching a maximum at 100 nM (1.82-fold stimulation), but no significant effect was found in SW-adapted eels (ANOVA: P<0.001 and P>0.05 respectively). Isolated tubule cells stimulated with 100 nM Ang II showed a significant generation of inositol trisphosphate (InsP(3)) and an increment in calcium release from intracellular stores. In conclusion, our results suggest that tubular Na(+)/K(+)ATPase is modulated by environmental salinity, and that Ang II has a role in regulating its activity in FW-adapted eels, probably through an InsP(3)-dependent mechanism.
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Tishkoff, Daniel X., Karl A. Nibbelink, Kristina H. Holmberg, Loredana Dandu und Robert U. Simpson. „Functional Vitamin D Receptor (VDR) in the T-Tubules of Cardiac Myocytes: VDR Knockout Cardiomyocyte Contractility“. Endocrinology 149, Nr. 2 (01.11.2007): 558–64. http://dx.doi.org/10.1210/en.2007-0805.
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We have previously shown that the active form of vitamin D, 1,25 dihydroxyvitamin D3 [1,25(OH)2D3], has both genomic and rapid nongenomic effects in heart cells; however, the subcellular localization of the vitamin D receptor (VDR) in heart has not been studied. Here we show that in adult rat cardiac myocytes the VDR is primarily localized to the t-tubule. Using immunofluorescence and Western blot analysis, we show that the VDR is closely associated with known t-tubule proteins. Radioligand binding assays using 3H-labeled 1,25(OH)2D3 demonstrate that a t-tubule membrane fraction isolated from homogenized rat ventricles contains a 1,25(OH)2D3-binding activity similar to the classic VDR. For the first time, we show that cardiac myocytes isolated from VDR knockout mice show accelerated rates of contraction and relaxation as compared with wild type and that 1,25(OH)2D3 directly affects contractility in the wild-type but not the knockout cardiac myocyte. Moreover, we observed that acute (5 min) exposure to 1,25(OH)2D3 altered the rate of relaxation. A receptor localized to t-tubules in the heart is ideally positioned to exert an immediate effect on signal transduction mediators and ion channels. This novel discovery is fundamentally important in understanding 1,25(OH)2D3 signal transduction in heart cells and provides further evidence that the VDR plays a role in heart structure and function.
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Brette, Fabien, und Clive Orchard. „T-Tubule Function in Mammalian Cardiac Myocytes“. Circulation Research 92, Nr. 11 (13.06.2003): 1182–92. http://dx.doi.org/10.1161/01.res.0000074908.17214.fd.
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Ahbab, Müfide Aydoğan, Nurhayat Barlas und Gözde Karabulut. „The toxicological effects of bisphenol A and octylphenol on the reproductive system of prepubertal male rats“. Toxicology and Industrial Health 33, Nr. 2 (10.07.2016): 133–46. http://dx.doi.org/10.1177/0748233715603847.
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The aim of the present study was to assess and compare the individual adverse effects of bisphenol A (BPA) and octylphenol (OP) on the reproductive system of prepubertal male rats. Rats were exposed to BPA and OP at doses of 125 and 250 mg/kg/day, by gavage, for 90 days. At the end of the study, the testes, epididymis, prostate gland, and seminal vesicle were removed and examined histopathologically. Also, 3-β-hydroxysteroid dehydrogenase expressions were analyzed and serum testosterone and luteinizing hormone (LH) levels were measured. Sperm head count of caput epididymis was performed using a hemocytometer. Seminiferous and epididymal round tubules were evaluated for tubule diameter, lumen diameter, and height of tubule epithelium. There were significant increases in relative testes weights in BPA125, OP125, and OP250 groups compared with the control. Atrophic tubules, pyknotic tubules, combined tubules, congestion, vacuolization of Sertoli cell, cell debris in the lumen, tubules without sperm, and degeneration of tubules were noted in the tissue specimens obtained from the treatment groups compared with the control group. Sperm head counts were decreased in all treatment groups except for the low-dose BPA group. Testosterone (T) levels decreased in the BPA and high-dose OP treatment groups. LH levels increased in BPA treatment groups and the low-dose OP treatment group and decreased in the high-dose OP group. Epithelial height of high-dose BPA and OP treatment groups increased compared with the control group. Furthermore tubular height of low-dose BPA and high-dose OP groups increased with respect to control levels. In the OP250 treatment group, thyroxine hormone level was increased compared to other groups. Also, in the OP125 treatment group, triiodothyronine hormone level was increased compared with other groups. The results of this study showed that BPA and OP affect the steroidogenic enzyme expression and T production in Leydig cells. In conclusion, BPA and OP have adverse effects on the male reproductive system of prepubertal rats.
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Anderson, K., und G. Meissner. „T-tubule depolarization-induced SR Ca2+ release is controlled by dihydropyridine receptor- and Ca(2+)-dependent mechanisms in cell homogenates from rabbit skeletal muscle.“ Journal of General Physiology 105, Nr. 3 (01.03.1995): 363–83. http://dx.doi.org/10.1085/jgp.105.3.363.
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In vertebrate skeletal muscle, the voltage-dependent mechanism of rapid sarcoplasmic reticulum (SR) Ca2+ release, commonly referred to as excitation-contraction (EC) coupling, is believed to be mediated by physical interaction between the transverse (T)-tubule voltage-sensing dihydropyridine receptor (DHPR) and the SR ryanodine receptor (RyR)/Ca2+ release channel. In this study, differential T-tubule and SR membrane monovalent ion permeabilities were exploited with the use of an ion-replacement protocol to study T-tubule depolarization-induced SR 45Ca2+ release from rabbit skeletal muscle whole-cell homogenates. Specificity of Ca2+ release was ascertained with the use of the DHPR antagonists D888, nifedipine and PN200-110. In the presence of the "slow" complexing Ca2+ buffer EGTA, homogenates exhibited T-tubule depolarization-induced Ca2+ release comprised of an initial rapid phase followed by a slower release phase. During the rapid phase, approximately 20% of the total sequestered Ca2+ (approximately 30 nmol 45Ca2+/mg protein), corresponding to 100% of the caffeine-sensitive Ca2+ pool, was released within 50 ms. Rapid release could be inhibited fourfold by D888. Addition to release media of the "fast" complexing Ca2+ buffer BAPTA, at concentrations > or = 4 mM, nearly abolished rapid Ca2+ release, suggesting that most was Ca2+ dependent. Addition of millimolar concentrations of either Ca2+ or Mg2+ also greatly reduced rapid Ca2+ release. These results show that T-tubule depolarization-induced SR Ca2+ release from rabbit skeletal muscle homogenates is controlled by T-tubule membrane potential- and by Ca(2+)-dependent mechanisms.
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Twombley, Katherine, Jyothsna Gattineni, Ion Alexandru Bobulescu, Vangipuram Dwarakanath und Michel Baum. „Effect of metabolic acidosis on neonatal proximal tubule acidification“. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 299, Nr. 5 (November 2010): R1360—R1368. http://dx.doi.org/10.1152/ajpregu.00007.2010.
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The serum bicarbonate in neonates is lower than adults due in large part to a lower rate of proximal tubule acidification. It is unclear if the neonatal proximal tubule is functioning at maximal capacity or if the proximal tubule can respond to metabolic acidosis as has been described in adult proximal tubules. We find that neonatal mouse brush-border membranes have a lower Na+/H+ exchanger (NHE) 3 protein abundance (neonate 0.11 ± 0.05 vs. adult 0.64 ± 0.07; P < 0.05) and a higher NHE8 protein abundance (neonate 1.0 ± 0.01 vs. adult 0.13 ± 0.09; P < 0.001) compared with adults. To examine if neonates can adapt to acidosis, neonatal mice were gavaged with either acid or vehicle for 4 days, resulting in a drop in serum bicarbonate from 19.5 ± 1.0 to 8.9 ± 0.6 meq/l ( P < 0.001). Proximal convoluted tubule Na+/H+ exchanger activity (dpHi/d t) was 1.68 ± 0.19 pH units/min in control tubules and 2.49 ± 0.60 pH units/min in acidemic neonatal mice ( P < 0.05), indicating that the neonatal proximal tubule can respond to metabolic acidosis with an increase in Na+/H+ exchanger activity. Similarly, brush-border membrane vesicles from neonatal rats had an increase in Na+/H+ exchanger activity with acidemia that was almost totally inhibited by 10−6 M 5-( N-ethyl- n-isopropyl)-amiloride, a dose that has little effect on NHE3 but inhibits NHE8. There was a significant increase in both NHE3 (vehicle 0.35 ± 0.07 vs. acid 0.73 ± 0.07; P < 0.003) and NHE8 brush-border membrane protein abundance (vehicle 0.41 ± 0.05 vs. acid 0.73 ± 0.06; P < 0.001) in acidemic mouse neonates compared with controls. A comparable increase in NHE3 and NHE8 was found in neonatal rats with acidosis. In conclusion, the neonatal proximal tubule can adapt to metabolic acidosis with an increase in Na+/H+ exchanger activity.
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TAKESHIMA, Hiroshi, Misa SHIMUTA, Shinji KOMAZAKI, Kazuhiro OHMI, Miyuki NISHI, Masamitsu IINO, Atsuro MIYATA und Kenji KANGAWA. „Mitsugumin29, a novel synaptophysin family member from the triad junction in skeletal muscle“. Biochemical Journal 331, Nr. 1 (01.04.1998): 317–22. http://dx.doi.org/10.1042/bj3310317.
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In skeletal muscle, excitation–contraction (E–C) coupling requires the conversion of the depolarization signal of the invaginated surface membrane, namely the transverse (T-) tubule, to Ca2+ release from the sarcoplasmic reticulum (SR). Signal transduction occurs at the junctional complex between the T-tubule and SR, designated as the triad junction, which contains two components essential for E–C coupling, namely the dihydropyridine receptor as the T-tubular voltage sensor and the ryanodine receptor as the SR Ca2+-release channel. However, functional expression of the two receptors seemed to constitute neither the signal-transduction system nor the junction between the surface and intracellular membranes in cultured cells, suggesting that some as-yet-unidentified molecules participate in both the machinery. In addition, the molecular basis of the formation of the triad junction is totally unknown. It is therefore important to examine the components localized to the triad junction. Here we report the identification using monoclonal antibody and primary structure by cDNA cloning of mitsugumin29, a novel transmembrane protein from the triad junction in skeletal muscle. This protein is homologous in amino acid sequence and shares characteristic structural features with the members of the synaptophysin family. The subcellular distribution and protein structure suggest that mitsugumin29 is involved in communication between the T-tubular and junctional SR membranes.
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Cheng, Lu-Feng, Fuzhen Wang und Anatoli N. Lopatin. „Metabolic stress in isolated mouse ventricular myocytes leads to remodeling of t tubules“. American Journal of Physiology-Heart and Circulatory Physiology 301, Nr. 5 (November 2011): H1984—H1995. http://dx.doi.org/10.1152/ajpheart.00304.2011.
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Cardiac ventricular myocytes possess an extensive t-tubular system that facilitates the propagation of membrane potential across the cell body. It is well established that ionic currents at the restricted t-tubular space may lead to significant changes in ion concentrations, which, in turn, may affect t-tubular membrane potential. In this study, we used the whole cell patch-clamp technique to study accumulation and depletion of t-tubular potassium by measuring inward rectifier potassium tail currents ( IK1,tail), and inward rectifier potassium current ( IK1) “inactivation”. At room temperatures and in the absence of Mg2+ ions in pipette solution, the amplitude of IK1,tail measured ∼10 min after the establishment of whole cell configuration was reduced by ∼18%, but declined nearly twofold in the presence of 1 mM cyanide. At ∼35°C IK1,tail was essentially preserved in intact cells, but its amplitude declined by ∼85% within 5 min of cell dialysis, even in the absence of cyanide. Intracellular Mg2+ ions played protective role at all temperatures. Decline of IK1,tail was accompanied by characteristic changes in its kinetics, as well as by changes in the kinetics of IK1 inactivation, a marker of depletion of t-tubular K+. The data point to remodeling of t tubules as the primary reason for the observed effects. Consistent with this, detubulation of myocytes using formamide-induced osmotic stress significantly reduced IK1,tail, as well as the inactivation of inward IK1. Overall, the data provide strong evidence that changes in t tubule volume/structure may occur on a short time scale in response to various types of stress.
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Ibrahim, Michael, und Cesare M. Terracciano. „Reversibility of T-tubule remodelling in heart failure: mechanical load as a dynamic regulator of the T-tubules“. Cardiovascular Research 98, Nr. 2 (23.01.2013): 225–32. http://dx.doi.org/10.1093/cvr/cvt016.
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Kelley, K. A., N. Agarwal, S. Reeders und K. Herrup. „Renal cyst formation and multifocal neoplasia in transgenic mice carrying the simian virus 40 early region.“ Journal of the American Society of Nephrology 2, Nr. 1 (Juli 1991): 84–97. http://dx.doi.org/10.1681/asn.v2184.
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Simian virus 40 early region transgenic mice develop characteristic pathological abnormalities of the brain, kidney, and thymus, due to expression of large-T antigen. Earlier studies have indicated that the most consistent effect of large-T antigen expression is the formation of choroid plexus papillomas in the brain and that thymic hyperplasia and various kidney abnormalities are less frequently observed. The renal lesions reportedly consist of numerous glomerular abnormalities and tubular proliferation. Surprisingly, an analysis of 21 simian virus 40 early region transgenic mice, which were produced for this study, revealed a much higher incidence of polycystic kidney disease as well as earlier development of T-antigen-induced abnormalities. In marked contrast to earlier observations, there is an apparent reduction in the glomerular number in the affected kidneys, whereas the remaining glomeruli appear normal. The most striking feature of the T-antigen-induced renal abnormalities was extensive hyperplasia of tubular epithelial cells which was most marked in the distal tubules; all tubule segments are involved in the most severely affected animals. In most cases, cysts lined with hyperplastic epithelium were observed and papillary structures protruding from the cyst lining were evident. Multiple areas of focal neoplasia were apparent, and, in the most severely affected animals, there were areas in which tumor had replaced normal renal parenchyma. These results strongly suggest that T-antigen-induced renal cyst and tumor formation are part of the same pathological process which is initially manifested as tubular epithelial hyperplasia.
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Rame, J. Eduardo, und Sergio Lavandero. „Subcellular Remodeling of the T-Tubule Membrane System“. Circulation 135, Nr. 17 (25.04.2017): 1646–50. http://dx.doi.org/10.1161/circulationaha.117.025319.
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Di Maio, Alessandro, Kimberly Karko, Rose M. Snopko, Rafael Mejía-Alvarez und Clara Franzini-Armstrong. „T-tubule formation in cardiacmyocytes: two possible mechanisms?“ Journal of Muscle Research and Cell Motility 28, Nr. 4-5 (17.10.2007): 231–41. http://dx.doi.org/10.1007/s10974-007-9121-x.
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Green, Howard J. „Membrane Excitability, Weakness, and Fatigue“. Canadian Journal of Applied Physiology 29, Nr. 3 (01.06.2004): 291–307. http://dx.doi.org/10.1139/h04-020.
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A failure in membrane excitability, defined as an inability of the sarcolemma and T-tubule to translate the neural discharge command into repetitive action potentials, represents an inviting cause of mechanical disfunction in both health and disease. A failure at this level would precipitate a disturbance in signal transmission between the T-tubule and the calcium release channels of the sarcoplasmic reticulum, resulting in reduced release of Ca2+, lower cytosolic free Ca2+ levels, and depressed myofibrillar activation and force generation. The ability of the sarcolemma and T-tubules to conduct repetitive action potentials is intimately dependent on active transport of Na+ and K+ following an action potential. The active transport of these cations is mediated by the Na+-K+-ATPase, an integral membrane protein that uses the energy from the hydrolysis of 1 ATP to transport 3Na+ out of the cell and 2K+ into the cell. A failure to recruit sufficient Na+-K+-ATPase activity during contractile activity could result in a rundown of the transmembrane gradients for Na+ and K+, leading to a loss of membrane excitability. The Na+-K+-ATPase activity depends on the amount and isoform composition of the protein, substrate availability, and acute regulatory factors. Each of these factors is examined as a potential cause of altered activation of the Na+-K+-ATPase activity and loss of membrane excitability in fatigue. Regular exercise represents a potent stimulus for upregulating Na+-K+-ATPase levels and for increasing the ability for cation transport across the sarcolemma and T-tubule membrane. As such, training may be a valuable tool in the management of fatigue in health and disease. Key words: muscle, Na+-K+-ATPase, isoforms, action potentials
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Powell, J. A., L. Petherbridge und B. E. Flucher. „Formation of triads without the dihydropyridine receptor alpha subunits in cell lines from dysgenic skeletal muscle.“ Journal of Cell Biology 134, Nr. 2 (15.07.1996): 375–87. http://dx.doi.org/10.1083/jcb.134.2.375.
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Muscular dysgenesis (mdg/mdg), a mutation of the skeletal muscle dihydropyridine receptor (DHPR) alpha 1 subunit, has served as a model to study the functions of the DHPR in excitation-contraction coupling and its role in triad formation. We have investigated the question of whether the lack of the DHPR in dysgenic skeletal muscle results in a failure of triad formation, using cell lines (GLT and NLT) derived from dysgenic (mdg/mdg) and normal (+/+) muscle, respectively. The lines were generated by transfection of myoblasts with a plasmid encoding a Large T antigen. Both cell lines express muscle-specific proteins and begin organization of sarcomeres as demonstrated by immunocytochemistry. Similar to primary cultures, dysgenic (GLT) myoblasts show a higher incidence of cell fusion than their normal counterparts (NLT). NLT myotubes develop spontaneous contractile activity, and fluorescent Ca2+ recordings show Ca2+ release in response to depolarization. In contrast, GLTs show neither spontaneous nor depolarization-induced Ca2+ transients, but do release Ca2+ from the sarcoplasmic reticulum (SR) in response to caffeine. Despite normal transverse tubule (T-tubule) formation, GLT myotubes lack the alpha 1 subunit of the skeletal muscle DHPR, and the alpha 2 subunit is mistargeted. Nevertheless, the ryanodine receptor (RyR) frequently develops its normal, clustered organization in the absence of both DHPR alpha subunits in the T-tubules. In EM, these RyR clusters correspond to T-tubule/SR junctions with regularly spaced feet. These findings provide conclusive evidence that interactions between the DHPR and RyR are not involved in the formation of triad junctions or in the normal organization of the RyR in the junctional SR.
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Kieval, R. S., R. J. Bloch, G. E. Lindenmayer, A. Ambesi und W. J. Lederer. „Immunofluorescence localization of the Na-Ca exchanger in heart cells“. American Journal of Physiology-Cell Physiology 263, Nr. 2 (01.08.1992): C545—C550. http://dx.doi.org/10.1152/ajpcell.1992.263.2.c545.
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We investigated the localization of the Na-Ca exchanger in fixed, isolated heart cells from rat and guinea pig using immunocytochemical methods with epifluorescence and confocal microscopy. We found that the Na-Ca exchanger is distributed throughout all membranes in contact with the extracellular space, including the sarcolemma, the transverse tubules (T-tubules), and the intercalated disks. Microscopic nonuniformities in the fluorescent labeling appear to reflect varying views of the membranes containing Na-Ca exchanger protein. Confocal thin-section imaging reveals a regular grid of discrete foci of fluorescence, which represent Na-Ca exchanger in T-tubules viewed en face. These foci are 1.80 +/- 0.01 microns apart from sarcomere to sarcomere and are aligned with the Z-line. Along each Z-line, these foci are spaced at 1.22 +/- 0.11-microns intervals. Longitudinal sections of the sarcolemma-T-tubule junction show a comblike appearance, with T-tubules extending inward from the heavily labeled sarcolemma. Our finding that the Na-Ca exchanger is widely distributed over the cell surface may provide further insight into the role of Na-Ca exchange in the heart.
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Murzilli, Stefania, Matteo Serano, Laura Pietrangelo, Feliciano Protasi und Cecilia Paolini. „Structural Adaptation of the Excitation–Contraction Coupling Apparatus in Calsequestrin1-Null Mice during Postnatal Development“. Biology 12, Nr. 8 (29.07.2023): 1064. http://dx.doi.org/10.3390/biology12081064.
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The precise arrangement and peculiar interaction of transverse tubule (T-tubule) and sarcoplasmic reticulum (SR) membranes efficiently guarantee adequate contractile properties of skeletal muscle fibers. Fast muscle fibers from mice lacking calsequestrin 1 (CASQ1) are characterized by the profound ultrastructural remodeling of T-tubule/SR junctions. This study investigates the role of CASQ1, an essential component of calcium release units (CRUs), in the postnatal development of muscle fibers. By using CASQ1-knockout mice, we examined the maturation of CRUs and the involvement of different junctional proteins in the juxtaposition of the membrane system. Our morphological investigation of both wild-type (WT) and CASQ1-null extensor digitorum longus (EDL) fibers, from 1 week to 4 months of age, yielded noteworthy findings. Firstly, we observed that the absence of CASQ1 hindered the full maturation of CRUs, despite the correct localization of key junctional components (ryanodine receptor, dihydropyridine receptor, and triadin) to the junctional SR in adult animals. Furthermore, analysis of protein expression profiles related to T-tubule biogenesis and organization (junctophilin 1, amphiphysin 2, caveolin 3, and mitsugumin 29) demonstrated delayed progression in their expression during postnatal development in the absence of CASQ1, suggesting the impaired maturation of CRUs. The absence of CASQ1 directly impacts the proper assembly of CRUs during development and influences the expression and coordination of other proteins involved in T-tubule biogenesis and organization.