Calcium signalling microdomains and the t-tubular system in atrial mycoytes: potential roles in cardiac disease and arrhythmias

Trafford, Andrew W.; Clarke, Jessica D.; Richards, Mark; Eisner, David; Dibb, Katharine M.

doi:10.1093/cvr/cvt018

Cited by 48 publications

(50 citation statements)

References 116 publications

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“…Indeed, atrial cardiomyocytes either completely lack or possess only a rudimentary T-tubule network compared with ventricular myocytes in smaller laboratory species, such as the mouse. 120 Because EPAC2 is mostly expressed in T tubules of mouse cardiomyocytes, 114 it is possible that EPAC1 deletion prevents atrial fibrillation. 110 In addition, EPAC isoform expression may vary in function of the cell type.…”

Section: Epac and Cardiac Electric Remodelingmentioning

confidence: 99%

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Lezoualc’h

Fazal

Laudette

et al. 2016

Circulation Research

146

143

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C yclic adenosine 3′,5′-monophosphate (cAMP) is one of the most studied signaling molecules that plays a critical role in cellular responses to extracellular stimuli in the cardiovascular system. It controls a wide range of biological effects, including cell proliferation, differentiation, and apoptosis. 1 cAMP is produced from ATP by transmembrane adenylyl cyclase on activation of Gs-coupled G protein-coupled receptors. 2In addition, soluble adenylyl cyclase is a second intracellular source of cAMP and can be activated by divalent cations in various subcellular compartments.3 The intracellular level of cAMP depends not only on its production by adenylyl cyclase but also its degradation by a large family of cAMP phosphodiesterases (PDEs), which catalyze the hydrolysis of cAMP into 5′-AMP. 4 PDEs are key actors in limiting the spread of cAMP and seem critical for the formation of dynamic microdomains that confer specific response to various hormones. 4 Besides specialized membrane structures that may also limit cAMP diffusion, A-kinase anchoring proteins function to tether cAMP effectors and PDEs enzymes into defined cellular compartments and, therefore, maintain localized pools of cAMP to control the cellular actions of the second messenger. 5Until recently, the intracellular effects of cAMP were attributed to the activation of protein kinase A (PKA) and cyclic nucleotide-gated ion channels. In 1998, a family of novel cAMP effector proteins named exchange proteins directly activated by cAMP (EPACs) was discovered. 6,7 The EPAC protein family is composed of EPAC1 and EPAC2, which act as guanine-nucleotide exchange factors (GEFs) for the small G proteins, Rap1 and Rap2, and function in a PKA-independent manner. 6,7 On binding to cAMP, EPAC promotes the exchange of GDP for GTP, thereby inducing the activation of the small G protein Rap.8 In contrast, Rap-GTPase-activating proteins enhance the intrinsic GTP hydrolysis activity of Rap leading to GTPase inactivation. 9The cycling of Rap between its inactive and active states provides a mechanism to regulate the binding to effector proteins.The discovery of EPAC proteins has broken the dogma surrounding cAMP and PKA, and uncovered new perspectives for the understanding of cAMP signaling in the cardiovascular system. The functions of these cAMP-sensitive GEFs in various subcellular compartments and cellular contexts are currently being unraveled, but given the availability of EPAC-specific ligands and engineered mouse models, a large body of evidence indicates that EPAC proteins are involved in multiple biological actions of cAMP, such as cardiac hypertrophy and vascular inflammation. In this review, after a description of EPAC protein structures and mechanism of activation, we discuss recent advances in the discovery of novel pharmacological modulators of EPAC (Figure 1). We provide an overview of the roles of EPAC proteins, their signalosome and compartmentation in cardiovascular function and diseases. We also discuss the therapeutic potential of EPAC ligands in the t...

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Section: Epac and Cardiac Electric Remodelingmentioning

confidence: 99%

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Lezoualc’h

Fazal

Laudette

et al. 2016

Circulation Research

146

143

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“…T-tubules were recently documented in sheep and human AMs 22 . Current evidence suggests that few T-tubules exist in AM cells and typically in larger mammals like sheep and humans, but not in small rodents 23 . In contrast to VMs, in AMs intracellular Ca 2+ release appears to occur from the cell surface propagating by diffusion towards the cell center which results in marked spatial and temporal Ca 2+ gradients 23 .…”

mentioning

confidence: 93%

“…Current evidence suggests that few T-tubules exist in AM cells and typically in larger mammals like sheep and humans, but not in small rodents 23 . In contrast to VMs, in AMs intracellular Ca 2+ release appears to occur from the cell surface propagating by diffusion towards the cell center which results in marked spatial and temporal Ca 2+ gradients 23 . Within this framework it seems important to elucidate mechanisms of intracellular Ca 2+ signaling instability for common disease forms such as atrial fibrillation 24 .…”

mentioning

confidence: 93%

Analysis of Tubular Membrane Networks in Cardiac Myocytes from Atria and Ventricles

Wagner

Brandenburg

Kohl

et al. 2014

JoVE

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In cardiac myocytes a complex network of membrane tubules -the transverse-axial tubule system (TATS) -controls deep intracellular signaling functions. While the outer surface membrane and associated TATS membrane components appear to be continuous, there are substantial differences in lipid and protein content. In ventricular myocytes (VMs), certain TATS components are highly abundant contributing to rectilinear tubule networks and regular branching 3D architectures. It is thought that peripheral TATS components propagate action potentials from the cell surface to thousands of remote intracellular sarcoendoplasmic reticulum (SER) membrane contact domains, thereby activating intracellular Ca 2+ release units (CRUs). In contrast to VMs, the organization and functional role of TATS membranes in atrial myocytes (AMs) is significantly different and much less understood. Taken together, quantitative structural characterization of TATS membrane networks in healthy and diseased myocytes is an essential prerequisite towards better understanding of functional plasticity and pathophysiological reorganization.Here, we present a strategic combination of protocols for direct quantitative analysis of TATS membrane networks in living VMs and AMs. For this, we accompany primary cell isolations of mouse VMs and/or AMs with critical quality control steps and direct membrane staining protocols for fluorescence imaging of TATS membranes. Using an optimized workflow for confocal or superresolution TATS image processing, binarized and skeletonized data are generated for quantitative analysis of the TATS network and its components. Unlike previously published indirect regional aggregate image analysis strategies, our protocols enable direct characterization of specific components and derive complex physiological properties of TATS membrane networks in living myocytes with high throughput and open access software tools. In summary, the combined protocol strategy can be readily applied for quantitative TATS network studies during physiological myocyte adaptation or disease changes, comparison of different cardiac or skeletal muscle cell types, phenotyping of transgenic models, and pharmacological or therapeutic interventions.

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“…Taking into consideration the differences in cardiac Ca 2+ handling between rats and guinea pigs (32), atria and ventricles (33), and small and large mammals (27), ultrastructural alterations of the cardiomyocytes in the hearts of rats, guinea pigs and Landrace pigs in previously reported acute conditions (15,16,30,31) to induce Ca 2+ disturbances and arrhythmias were explored.…”

Section: Methodsmentioning

confidence: 99%

“…Prolonged duration of AF leads to difficulties in conversion into sinus rhythm and maintainance of sinus rhythm after successful conversion. It is due to abnormal Ca 2+ handling as well as pronounced structural and electrophysiological remodelling in chronic AF (23)(24)(25)27).…”

mentioning

confidence: 99%

Disorders of Ca2+ handling and cell-to-cell coupling are implicated in the development of acute heart failure in intact animal hearts: An ultrastructural study

Tribulová¹,

Knézl²,

Bačová³

et al. 2015

Curr Res Cardiol

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bACKgRoUND: It has been previously reported that various acute interventions causing myocardial abnormalities in Ca 2+ handling and defects in intercellular coupling facilitate the occurrence of malignant arrhythmias. objECTIVES: To comprehensively determine the impact of such Ca 2+ -related disorders induced in intact animal hearts on the ultrastructure of the cardiomyocytes before occurrence and during sustaining of severe arrhythmias. METhoDS: Three types of acute experiments known to be accompanied by disturbances in Ca 2+ handling were performed. Langendorff-perfused rat and guinea pig hearts were subjected to K + -deficient perfusion to induce ventricular fibrillation; Langendorff-perfused guinea pig heart underwent burst atrial pacing to induce atrial fibrillation; and open chest pig heart was used for intramyocardial noradrenaline infusion to induce ventricular tachycardia. Tissue samples for electron microscopy examination were obtained during basal conditions, previous occurrence and during sustaining of malignant arrhythmias. RESUlTS:The comparative findings suggest that myocardial heterogeneity of high [Ca 2+ ]i-induced subcellular injury of the cardiomyocytes and their junctions is a common feature that precede occurrence ventricular tachycardia, ventricular fibrillation or atrial fibrillation regardless of the species and atria/ventricular-related differences in Ca 2+ handling and intercellular coupling. The primary changes consisted of nonuniform sarcomere shortening, which most likely reflects cytosolic Ca 2+ oscillations; disturbances in Ca 2+ wave propagation; and Ca 2+ overload. These disturbances were linked with defects in cardiac cell-to-cell coupling that increased the propensity of the heart to malignant arrhythmias. Moreover, Ca 2+ overload led to disruption of myofilaments, jeopardizing contractile function. CoNClUSIoNS:The results provide a novel paradigm linking Ca 2+ -related arrhythmogenesis and contractility disorders that may contribute to acute heart failure.

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Calcium signalling microdomains and the t-tubular system in atrial mycoytes: potential roles in cardiac disease and arrhythmias

Cited by 48 publications

References 116 publications

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease

Analysis of Tubular Membrane Networks in Cardiac Myocytes from Atria and Ventricles

Disorders of Ca2+ handling and cell-to-cell coupling are implicated in the development of acute heart failure in intact animal hearts: An ultrastructural study

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