Cardiac Z-disc Signaling Network

Frank, Derk; Frey, Norbert

doi:10.1074/jbc.r110.174268

Cited by 156 publications

(145 citation statements)

References 101 publications

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“…The contractile sarcomeric units within the cardiomyocyte are delimited by the Z-disks that contain a large network of interacting proteins that ensure force transduction from the sarcomeric units to the sarcolemma, the extracellular matrix and to adjacent cardiomyocytes 9 . Integrin-linked kinase (ILK) is highly expressed in the sarcomeric Z-disk costamere (region of close intermyocyte linkage) and is a critical component of the protein scaffold required for integrated force transduction during normal cardiac function [10][11][12] .…”

mentioning

confidence: 99%

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Traister

Aafaqi

et al. 2014

Nat Commun

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Human dilated cardiomyopathy (DCM) manifests as a profound reduction in biventricular cardiac function that typically progresses to death or cardiac transplantation. There is no effective mechanism-based therapy currently available for DCM, in part because the transduction of mechanical load into dynamic changes in cardiac contractility (termed mechanotransduction) remains an incompletely understood process during both normal cardiac function and in disease states. Here we show that the mechanoreceptor protein integrin-linked kinase (ILK) mediates cardiomyocyte force transduction through regulation of the key calcium regulatory protein sarcoplasmic/endoplasmic reticulum Ca 2 þ ATPase isoform 2a (SERCA-2a) and phosphorylation of phospholamban (PLN) in the human heart. A non-oncogenic ILK mutation with a synthetic point mutation in the pleckstrin homology-like domain (ILK R211A ) is shown to enhance global cardiac function through SERCA-2a/PLN. Thus, ILK serves to link mechanoreception to the dynamic modulation of cardiac contractility through a previously undiscovered interaction with the functional SERCA-2a/PLN module that can be exploited to rescue impaired mechanotransduction in DCM.

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mentioning

confidence: 99%

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Traister

Aafaqi

et al. 2014

Nat Commun

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“…The development of cardiomyopathy in humans and mouse models with mutations/defects in Z-disc proteins highlight the need to understand the molecular mechanisms that regulate Z-disc biology (2). A greater knowledge of the basic mechanisms responsible will be important for the development of improved therapeutic strategies for the heart.…”

Section: Discussionmentioning

confidence: 99%

“…A greater knowledge of the basic mechanisms responsible will be important for the development of improved therapeutic strategies for the heart. Z-disc proteins share "sticky" domains that are capable of mediating multiple protein-protein interactions and play an essential role in integrating structure and signaling in the complex three-dimensional network (2). Phosphatases and kinases, including calcineurin and protein kinase C, have been shown previously to reside at the Z-disc (2).…”

Section: Discussionmentioning

confidence: 99%

“…Maintenance of cardiac structure and Z-disc signaling are considered key factors responsible for protecting the heart in a setting of stress. Mutations of genes encoding proteins of the costamere and Z-disc have been linked with cardiomyopathies in animals and humans (1,2). Costameres are specialized membrane junctions that physically connect the Z-disc to the basal lamina outside of the cell.…”

mentioning

confidence: 99%

“…The Z-disc is well recognized for its role in maintaining structural integrity and, more recently, has emerged as a "hot spot" or nodal hub of cardiomyocyte signaling, converting mechanical signals into chemical signals, leading to a transcriptional response and induction of a cardiac phenotype such as hypertrophy (1). Despite progress in this area, the mechanisms responsible for regulating components of the costamere and Z-disc are not well defined (2).…”

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confidence: 99%

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Phosphoinositide 3-Kinase (PI3K(p110α)) Directly Regulates Key Components of the Z-disc and Cardiac Structure

Waardenberg

Bernardo

et al. 2011

Journal of Biological Chemistry

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Maintenance of cardiac structure and Z-disc signaling are key factors responsible for protecting the heart in a setting of stress, but how these processes are regulated is not well defined. We recently demonstrated that PI3K(p110␣) protects the heart against myocardial infarction. The aim of this study was to determine whether PI3K(p110␣) directly regulates components of the Z-disc and cardiac structure. To address this question, a unique three-dimensional virtual muscle model was applied to gene expression data from transgenic mice with increased or decreased PI3K(p110␣) activity under basal conditions (sham) and in a setting of myocardial infarction to display the location of structural proteins. Key findings from this analysis were then validated experimentally. The three-dimensional virtual muscle model visually highlighted reciprocally regulated transcripts associated with PI3K activation that encoded key components of the Z-disc and costamere, including melusin. Studies were performed to assess whether PI3K and melusin interact in the heart. Here, we identify a novel melusin-PI3K interaction that generates lipid kinase activity. The direct impact of PI3K(p110␣) on myocyte structure was assessed by treating neonatal rat ventricular myocytes with PI3K(p110␣) inhibitors and examining the myofiber morphology of hearts from PI3K transgenic mice. Results demonstrate that PI3K is critical for myofiber maturation and Z-disc alignment. In summary, PI3K regulates the expression of genes essential for cardiac structure and Z-disc signaling, interacts with melusin, and is critical for Z-disc alignment.An important question in cardiac biology is what makes one heart stronger, or more capable of resisting stress, than another. Maintenance of cardiac structure and Z-disc signaling are considered key factors responsible for protecting the heart in a setting of stress. Mutations of genes encoding proteins of the costamere and Z-disc have been linked with cardiomyopathies in animals and humans (1, 2). Costameres are specialized membrane junctions that physically connect the Z-disc to the basal lamina outside of the cell. The Z-disc is well recognized for its role in maintaining structural integrity and, more recently, has emerged as a "hot spot" or nodal hub of cardiomyocyte signaling, converting mechanical signals into chemical signals, leading to a transcriptional response and induction of a cardiac phenotype such as hypertrophy (1). Despite progress in this area, the mechanisms responsible for regulating components of the costamere and Z-disc are not well defined (2).The p110␣ isoform of phosphoinositide 3-kinase (PI3K-(p110␣)/PIK3CA) has cardioprotective properties (3). We recently demonstrated that cardiac expression of a constitutively active (ca) 3 PI3K transgene (increased PI3K activity) provided protection in a mouse model of myocardial infarction (MI), whereas a reduction in cardiac PI3K activity (utilizing a dominant negative (dn) PI3K transgene) accelerated the progression of heart failure (4). This makes target...

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Compartmentalization in cardiomyocytes modulates creatine kinase and adenylate kinase activities

Birkedal,

Branovets,

Vendelin

2024

FEBS Letters

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Intracellular molecules are transported by motor proteins or move by diffusion resulting from random molecular motion. Cardiomyocytes are packed with structures that are crucial for function, but also confine the diffusional spaces, providing cells with a means to control diffusion. They form compartments in which local concentrations are different from the overall, average concentrations. For example, calcium and cyclic AMP are highly compartmentalized, allowing these versatile second messengers to send different signals depending on their location. In energetic compartmentalization, the ratios of AMP and ADP to ATP are different from the average ratios. This is important for the performance of ATPases fuelling cardiac excitation‐contraction coupling and mechanical work. A recent study suggested that compartmentalization modulates the activity of creatine kinase and adenylate kinase in situ. This could have implications for energetic signaling through, for example, AMP‐activated kinase. It highlights the importance of taking compartmentalization into account in our interpretation of cellular physiology and developing methods to assess local concentrations of AMP and ADP to enhance our understanding of compartmentalization in different cell types.

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Cardiac Z-disc Signaling Network

Cited by 156 publications

References 101 publications

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Integrin-linked kinase mediates force transduction in cardiomyocytes by modulating SERCA2a/PLN function

Phosphoinositide 3-Kinase (PI3K(p110α)) Directly Regulates Key Components of the Z-disc and Cardiac Structure

Compartmentalization in cardiomyocytes modulates creatine kinase and adenylate kinase activities

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