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Mark B. Cannell - One of the best experts on this subject based on the ideXlab platform.
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Changes in the organization of Excitation-Contraction Coupling structures in failing human heart
'Public Library of Science (PLoS)', 2019Co-Authors: Dj Crossman, Peter R. Ruygrok, Soeller C, Mark B. CannellAbstract:This is the final version. Available from the publisher via the DOI in this record.Background: The cardiac myocyte t-tubular system ensures rapid, uniform cell activation and several experimental lines of evidence suggest changes in the t-tubular system and associated Excitation-Contraction Coupling proteins may occur in heart failure. Methods and Results: The organization of t-tubules, L-type calcium channels (DHPRs), ryanodine receptors (RyRs) and contractile machinery were examined in fixed ventricular tissue samples from both normal and failing hearts (idiopathic (non-ischemic) dilated cardiomyopathy) using high resolution fluorescent imaging. Wheat germ agglutinin (WGA), Na-Ca exchanger, DHPR and caveolin-3 labels revealed a shift from a predominantly transverse orientation to oblique and axial directions in failing myocytes. In failure, dilation of peripheral t-tubules occurred and a change in the extent of protein glycosylation was evident. There was no change in the fractional area occupied by myofilaments (labeled with phalloidin) but there was a small reduction in the number of RyR clusters per unit area. The general relationship between DHPRs and RyR was not changed and RyR labeling overlapped with 51±3% of DHPR labeling in normal hearts. In longitudinal (but not transverse) sections there was an ~30% reduction in the degree of colocalization between DHPRs and RyRs as measured by Pearson's correlation coefficient in failing hearts. Conclusions: The results show that extensive remodelling of the t-tubular network and associated Excitation-Contraction Coupling proteins occurs in failing human heart. These changes may contribute to abnormal calcium handling in heart failure. The general organization of the t-system and changes observed in failure samples have subtle differences to some animal models although the general direction of changes are generally similar. © 2011 Crossman et al.Health Research Council of New Zealan
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correction changes in the organization of Excitation Contraction Coupling structures in failing human heart
PLOS ONE, 2011Co-Authors: David J. Crossman, Peter R. Ruygrok, Christian Soeller, Mark B. CannellAbstract:The middle initial of the second author is incorrect. The correct spelling is: Peter N. Ruygrok. The correct citation is: Crossman DJ, Ruygrok PN, Soeller C, Cannell MB (2011) Changes in the Organization of Excitation-Contraction Coupling Structures in Failing Human Heart. PLoS ONE 6(3): e17901. doi:10.1371/journal.pone.0017901 The correct author contributions are: Conceived and designed the experiments: MBC DJC PNR. Performed the experiments: DJC. Analyzed the data: MBC DJC CS. Contributed reagents/materials/analysis tools: MBC CS PNR. Wrote the paper: DJC MBC.
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Changes in the Organization of Excitation-Contraction Coupling Structures in Failing Human Heart
PloS one, 2011Co-Authors: David J. Crossman, Peter R. Ruygrok, Christian Soeller, Mark B. CannellAbstract:The cardiac myocyte t-tubular system ensures rapid, uniform cell activation and several experimental lines of evidence suggest changes in the t-tubular system and associated Excitation-Contraction Coupling proteins may occur in heart failure.
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Excitation Contraction Coupling in the heart and the negative inotropic action of volatile anesthetics
Anesthesiology, 2004Co-Authors: Peter J Hanley, Henk E D J Ter Keurs, Mark B. CannellAbstract:IN a comprehensive review in 1987, Rusy and Komai discussed the possible mechanisms by which volatile anesthetics inhibit cardiac Contraction. Since that time, there have been advancements in the understanding of Excitation-Contraction Coupling, cardiac mechanics, and the actions of volatile anesthetics. There are essentially three major factors that determine the force of Contraction of heart muscle cells: the magnitude of cytosolic Ca increase after electrical Excitation, the responsiveness of the contractile proteins to Ca , and the sarcomere length (SL) at which the contractile proteins are activated. Hence, there are two possible ultimate direct negative inotropic actions of volatile anesthetics: a reduction in Ca availability or a decrease in the Ca responsiveness (Ca -sensitivity or maximal Ca -activated force) of the contractile apparatus. The rate of relaxation of the muscle cells, on the other hand, depends on the rate at which Ca is cleared from the cytosol, which facilitates its dissociation from the regulatory proteins of the contractile system. The control of calcium cycling and the activity of the contractile proteins consume energy that must be continuously supplied by the mitochondria, another potential site volatile of anesthetic action.
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relation between the sarcolemmal ca2 current and ca2 sparks and local control theories for cardiac Excitation Contraction Coupling
Circulation Research, 1996Co-Authors: Luis Fernando Santana, Ana Maria Gomez, Heping Cheng, Mark B. Cannell, W J LedererAbstract:Ca2+ sparks, the elementary events underlying Excitation-Contraction (E-C) Coupling, occur when sarcoplasmic reticulum (SR) Ca2+ release channels open. They are activated locally by Ca2+ influx through sarcolemmal (SL) Ca2+ channels. By measuring the probability of spark occurrence under conditions in which their probability of occurrence is low, we address two important questions raised by our recent work: (1) When a Ca2+ spark is triggered, how many SL Ca2+ channels (at a minimum) contribute to its activation? (2) What is the relation between the subcellular local [Ca2+], produced by the opening of SL Ca2+ channels and the consequent SR Ca2+ release? By comparing the voltage dependence of Ca2+ sparks in rat ventricular myocytes with the Ca2+ current, we show that the opening of a single SL Ca2+ channel can trigger a Ca2+ spark. Furthermore, we deduce that the probability of SR Ca2+ release depends of the square of the local [Ca2+]i produced by SL Ca2+ channel openings. These results are discussed with respect to the properties of Ca2+-induced Ca2+-release (CICR) and the local control theory of Excitation-Contraction Coupling.
Christine L Mummery - One of the best experts on this subject based on the ideXlab platform.
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simultaneous measurement of Excitation Contraction Coupling parameters identifies mechanisms underlying contractile responses of hipsc derived cardiomyocytes
Nature Communications, 2019Co-Authors: Berend J Van Meer, Ana Krotenberg, Luca Sala, Richard P Davis, Thomas Eschenhagen, Chris Denning, Leon G J Tertoolen, Christine L MummeryAbstract:Cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) are increasingly recognized as valuable for determining the effects of drugs on ion channels but they do not always accurately predict contractile responses of the human heart. This is in part attributable to their immaturity but the sensitivity of measurement tools may also be limiting. Measuring action potential, calcium flux or Contraction individually misses critical information that is captured when interrogating the complete Excitation-Contraction Coupling cascade simultaneously. Here, we develop an hypothesis-based statistical algorithm that identifies mechanisms of action. We design and build a high-speed optical system to measure action potential, cytosolic calcium and Contraction simultaneously using fluorescent sensors. These measurements are automatically processed, quantified and then assessed by the algorithm. Multiplexing these three critical physical features of hiPSC-CMs allows identification of all major drug classes affecting contractility with detection sensitivities higher than individual measurement of action potential, cytosolic calcium or Contraction.
Marian B Meyers - One of the best experts on this subject based on the ideXlab platform.
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expression of a sorcin missense mutation in the heart modulates Excitation Contraction Coupling
The FASEB Journal, 2007Co-Authors: Leon Collis, William A Coetzee, Colin K L Phoon, Eric A Sobie, Marian B Meyers, Jie Zhang, Glenn I FishmanAbstract:Sorcin is a Ca2+ binding protein implicated in the regulation of intracellular Ca2+ cycling and cardiac Excitation-Contraction Coupling. Structural and human genetic studies suggest that a naturally occurring sequence variant encoding L112-sorcin disrupts an E-F hand Ca2+ binding domain and may be responsible for a heritable form of hypertension and hypertrophic heart disease. We generated transgenic mice overexpressing L112-sorcin in the heart and characterized the effects on Ca2+ regulation and cardiac function both in vivo and in dissociated cardiomyocytes. Hearts of sorcinF112L transgenic mice were mildly dilated but ventricular function was preserved and systemic blood pressure was normal. SorcinF112L myocytes were smaller than control cells and displayed complex alterations in Ca2+ regulation and contractility, including a slowed inactivation of L-type Ca2+ current, enhanced Ca2+ spark width, duration, and frequency, and increased Na+-Ca2+ exchange activity. In contrast, mice with cardiac-specific o...
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effects of adenovirus mediated sorcin overexpression on Excitation Contraction Coupling in isolated rabbit cardiomyocytes
Circulation Research, 2003Co-Authors: Tim Seidler, Stefan Wagner, Stewart L W Miller, Christopher M Loughrey, Astrid Kania, Annika Burow, Sarah Kettlewell, Nils Teucher, Harald Kogler, Marian B MeyersAbstract:To evaluate the effect of sorcin on cardiac Excitation-Contraction Coupling, adult rabbit ventricular myocytes were transfected with a recombinant adenovirus coding for human sorcin (Ad-sorcin). A β-galactosidase adenovirus (Ad-LacZ) was used as a control. Fractional shortening in response to 1-Hz field stimulation (at 37°C) was significantly reduced in Ad-sorcin–transfected myocytes compared with control myocytes (2.10±0.05% [n=311] versus 2.42±0.06% [n=312], respectively; P P 2+ ] i was observed after Ad-sorcin transfection. L-type Ca 2+ current amplitude and time course were unaffected. Caffeine-induced Ca 2+ release from the sarcoplasmic reticulum (SR) and the accompanying inward Na + -Ca 2+ exchanger (NCX) current revealed a significantly lower SR Ca 2+ content and faster Ca 2+ -extrusion kinetics in Ad-sorcin–transfected cells. Higher NCX activity after Ad-sorcin transfection was confirmed by measuring the NCX current-voltage relationship. β-Escin–permeabilized rabbit cardiomyocytes were used to study the effects of sorcin overexpression on Ca 2+ sparks imaged with fluo 3 at 145 to 160 nmol/L [Ca 2+ ] using a confocal microscope. Under these conditions, caffeine-mediated SR Ca 2+ release was not different between the two groups. Spontaneous spark frequency, duration, width, and amplitude were lower in sorcin-overexpressing myocytes. In summary, sorcin overexpression in rabbit cardiomyocytes decreased Ca 2+ -transient amplitude predominately by lowering SR Ca 2+ content via increased NCX activity. The effect of sorcin overexpression on Ca 2+ sparks indicates an effect on the ryanodine receptor that may also influence Excitation-Contraction Coupling.
Aleksey V Zima - One of the best experts on this subject based on the ideXlab platform.
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ca handling during Excitation Contraction Coupling in heart failure
Pflügers Archiv: European Journal of Physiology, 2014Co-Authors: Aleksey V Zima, Elisa Bovo, Stefan R Mazurek, Jennifer A Rochira, Dmitry TerentyevAbstract:In the heart, Coupling between Excitation of the surface membrane and activation of contractile apparatus is mediated by Ca released from the sarcoplasmic reticulum (SR). Several components of Ca machinery are perfectly arranged within the SR network and the T-tubular system to generate a regular Ca cycling and thereby rhythmic beating activity of the heart. Among these components, ryanodine receptor (RyR) and SR Ca ATPase (SERCA) complexes play a particularly important role and their dysfunction largely underlies abnormal Ca homeostasis in diseased hearts such as in heart failure. The abnormalities in Ca regulation occur at practically all main steps of Ca cycling in the failing heart, including activation and termination of SR Ca release, diastolic SR Ca leak, and SR Ca uptake. The contributions of these different mechanisms to depressed contractile function and enhanced arrhythmogenesis may vary in different HF models. This brief review will therefore focus on modifications in RyR and SERCA structure that occur in the failing heart and how these molecular modifications affect SR Ca regulation and Excitation–Contraction Coupling.
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inositol 1 4 5 trisphosphate dependent ca2 signalling in cat atrial Excitation Contraction Coupling and arrhythmias
The Journal of Physiology, 2004Co-Authors: Aleksey V Zima, Lothar A BlatterAbstract:Inositol-1,4,5-trisphosphate (IP3)-dependent Ca2+ release represents the major Ca2+ mobilizing pathway responsible for diverse functions in non-excitable cells. In the heart, however, its role is largely unknown or controversial. In intact cat atrial myocytes, endothelin (ET-1) increased basal [Ca2+]i levels, enhanced action potential-evoked [Ca2+]i transients, caused [Ca2+]i transients with alternating amplitudes (Ca2+ alternans), and facilitated spontaneous Ca2+ release from the sarcoplasmic reticulum (SR) in the form of Ca2+ sparks and arrhythmogenic Ca2+ waves. These effects were prevented by the IP3 receptor (IP3R) blocker aminoethoxydiphenyl borate (2-APB), suggesting the involvement of IP3-dependent SR Ca2+ release. In saponin-permeabilized myocytes IP3 and the more potent IP3R agonist adenophostin increased basal [Ca2+]i and the frequency of spontaneous Ca2+ sparks. In the presence of tetracaine to eliminate Ca2+ release from ryanodine receptor (RyR) SR Ca2+ release channels, IP3 and adenophostin triggered unique elementary, non-propagating IP3R-dependent Ca2+ release events with amplitudes and kinetics that were distinctly different from classical RyR-dependent Ca2+ sparks. The effects of IP3 and adenophostin were prevented by heparin and 2-APB. The data suggest that IP3-dependent Ca2+ release increases [Ca2+]i in the vicinity of RyRs and thus facilitates Ca2+-induced Ca2+ release during Excitation–Contraction Coupling. It is concluded that in the adult mammalian atrium IP3-dependent Ca2+ release enhances atrial Ca2+ signalling and exerts a positive inotropic effect. In addition, by facilitating Ca2+ release, IP3 may also be an important component in the development of Ca2+-mediated atrial arrhythmias.
Martin D Bootman - One of the best experts on this subject based on the ideXlab platform.
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comparison of the t tubule system in adult rat ventricular and atrial myocytes and its role in Excitation Contraction Coupling and inotropic stimulation
Cell Calcium, 2010Co-Authors: Ioannis Smyrnias, Waltraud Mair, Dagmar Harzheim, Simon Walker, Llewelyn H Roderick, Martin D BootmanAbstract:Narrow, tubular, inward projections of the sarcolemma ('T-tubules') are an established feature of adult mammalian ventricular myocytes that enables them to generate the whole-cell Ca2+ transients and produce coordinated Contraction. Loss of T-tubules can occur during ageing and under pathological conditions, leading to altered cardiac Excitation-Contraction Coupling. In contrast to adult ventricular cells, atrial myocytes do not generally express an extensive T-tubule system at any stage of development, and therefore rely on Ca2+ channels around their periphery for the induction of Ca2+ signalling and Excitation-Contraction Coupling. Consequently, the characteristics of systolic Ca2+ signals in adult ventricular and atrial myocytes are temporally and spatially distinct. However, although atrial myocytes do not have the same regularly spaced convoluted T-tubule structures as adult ventricular cells, it has been suggested that a proportion of adult atrial cells have a more rudimentary tubule system. We examined the structure and function of these atrial tubules, and explored their impact on the initiation and recovery of Ca2+ signalling in electrically paced myocytes. The atrial responses were compared to those in adult ventricular cells that had intact T-tubules, or that had been chemically detubulated. We found that tubular structures were present in a significant minority of adult atrial myocytes, and were unlike the T-tubules in adult ventricular cells. In those cells where they were present, the atrial tubules significantly altered the on-set, amplitude, homogeneity and recovery of Ca2+ transients. The properties of adult atrial myocyte Ca2+ signals were different from those in adult ventricular cells, whether intact or detubulated. Excitation-Contraction Coupling in detubulated adult ventricular myocytes, therefore, does not approximate to atrial signalling, even though Ca2+ signals are initiated in the periphery of the cells in both of these situations. Furthermore, inotropic responses to endothelin-1 were entirely dependent on T-tubules in adult ventricular myocytes, but not in atrial cells. Our data reveal that that the T-tubules in atrial cells impart significant functional properties, but loss of these tubular membranes does not affect Ca2+ signalling as dramatically as detubulation in ventricular myocytes.
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functional insp3 receptors that may modulate Excitation Contraction Coupling in the heart
Current Biology, 2000Co-Authors: Peter Lipp, Mika Laine, Stephen C Tovey, Kylie M Burrell, Michael J Berridge, Martin D BootmanAbstract:The roles of the Ca2+-mobilising messenger inositol 1,4,5-trisphosphate (InsP3) in heart are unclear, although many hormones activate InsP3 production in cardiomyocytes and some of their inotropic, chronotropic and arrhythmogenic effects may be due to Ca2+ release mediated by InsP3 receptors (InsP3Rs) [1-3]. In the present study, we examined the expression and subcellular localisation of InsP3R isoforms, and investigated their potential role in modulating Excitation-Contraction Coupling (EC Coupling). Western, PCR and InsP3-binding analysis indicated that both atrial and ventricular myocytes expressed mainly type II InsP3Rs, with approximately sixfold higher levels of InsP3Rs in atrial cells. Co-immunostaining of atrial myocytes with antibodies against type II ryanodine receptors (RyRs) and type II InsP3Rs revealed that the latter were arranged in the subsarcolemmal space where they largely co-localised with the junctional RyRs. Stimulation of quiescent or electrically paced atrial myocytes with a membrane-permeant InsP3 ester, which enters cells and directly activates InsP3Rs, caused the appearance of spontaneous Ca2+-release events. In addition, in paced cells, the InsP3 ester evoked an increase in the amplitudes of action potential-evoked Ca2+ transients. These data indicate that atrial cardiomyocytes express functional InsP3Rs, and that these channels could modulate EC Coupling.
