Calcium Biology of the Transverse Tubules in Heart

Song, Long‐Sheng; Guatimosim, Sílvia; Gómez-Víquez, Leticia; Sobie, Eric A.; Ziman, Andrew P.; Hartmann, Hali A.; Lederer, W. Jonathan

doi:10.1196/annals.1341.009

Cited by 56 publications

(47 citation statements)

References 50 publications

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“…Traditionally, PI3K activation leads to phosphorylation of Akt, thereby regulating the activity of several cellular processes including transcription, cell proliferation, glucose metabolism, apoptosis and cell migration (Katso et al, 2001;Song et al, 2005). Our studies here have shown that reduced Vcl inhibited PI3K activation in cardiac myocytes.…”

Section: Novel Role Of Vcl In Pi3k/akt Signalingsupporting

confidence: 52%

Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin 43 containing gap junctions in cardiac Myocytes

Zemljic-Harpf

Godoy

Platoshyn

et al. 2014

Journal of Cell Science

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Vinculin (Vcl) links actin filaments to integrin-and cadherin-based cellular junctions. Zonula occludens-1 (ZO-1, also known as TJP1) binds connexin-43 (Cx43, also known as GJA1), cadherin and actin. Vcl and ZO-1 anchor the actin cytoskeleton to the sarcolemma. Given that loss of Vcl from cardiomyocytes causes maldistribution of Cx43 and predisposes cardiomyocyte-specific Vcl-knockout mice with preserved heart function to arrhythmia and sudden death, we hypothesized that Vcl and ZO-1 interact and that loss of this interaction destabilizes gap junctions. We found that Vcl, Cx43 and ZO-1 colocalized at the intercalated disc. Loss of cardiomyocyte Vcl caused parallel loss of ZO-1 from intercalated dics. Vcl coimmunoprecipitated Cx43 and ZO-1, and directly bound ZO-1 in yeast two-hybrid studies. Excision of the Vcl gene in neonatal mouse cardiomyocytes caused a reduction in the amount of Vcl mRNA transcript and protein expression leading to (1) decreased protein expression of Cx43, ZO-1, talin, and b1D-integrin, (2) reduced PI3K activation, (3) increased activation of Akt, Erk1 and Erk2, and (4) cardiomyocyte necrosis. In summary, this is the first study showing a direct interaction between Vcl and ZO-1 and illustrates how Vcl plays a crucial role in stabilizing gap junctions and myocyte integrity.

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Section: Novel Role Of Vcl In Pi3k/akt Signalingsupporting

confidence: 52%

Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin 43 containing gap junctions in cardiac Myocytes

Zemljic-Harpf

Godoy

Platoshyn

et al. 2014

Journal of Cell Science

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“…1). This transverse tubular system (t-tubules, [182]) facilitates the spatial and temporal coordination of CICR during an AP, resulting in the summation of a large number of Ca 2+ sparks, whose activation is a stochastic process [31]. In contrast, atrial myocytes lack t-tubules and thus, Ca 2+ -transients initiate in the periphery of the cell and then spread centripetally [20,110,119].…”

Section: Excitation-contraction Couplingmentioning

confidence: 99%

Excitation-contraction coupling and mitochondrial energetics

Maack

O’Rourke²

2007

Basic Res Cardiol

221

183

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Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, P i , and Ca 2+ . However, the kinetics of mitochondrial Ca 2+ -uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca 2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca 2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca 2+ microdomain could explain seemingly controversial results on mitochondrial Ca 2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca 2+ uptake facilitated by microdomains may shape cytosolic Ca 2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca 2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. Keywords calcium; sodium; microdomain; heart failure; adenosine triphosphate; adenosine diphosphate; respiration; tricarboxylic acid cycle Physiological aspectsThe most important function of the heart is to pump blood to supply the body with oxygen and substrates. In order to adapt cardiac output to the constantly changing demand of blood supply, the heart utilizes three major mechanisms to increase cardiac output: the force-frequency relationship (the Bowditch effect or Treppe; [22]), the Frank-Starling mechanism (sarcomere length-dependent activation of contractile force) [66,149,164], and sympathetic activation [28]. All of these mechanisms increase and accelerate myocardial force generation, and at the same time increase cellular energy demand. By these mechanisms, cardiac output during exertion can be increased more than five-fold compared to resting conditions. © Steinkopff Verlag 2007Correspondence to: Christoph Maack. NIH Public Access Excitation-contraction couplingOf fundamental importance for cardiac contraction and relaxation are the processes of excitation-contraction (EC) coupling (Fig. 1). During the action potential (AP), voltage-gated Na + -channels are activated, and the inward Na + -current (I Na ) induces a rapid depolarization of the cell membrane, facilitating voltage-dependent opening of L-type Ca 2+ -channels (I Ca,L ). The Ca 2+ influx triggers the opening of the ryanodine receptor (RyR2 subtype), inducing the release of even greater amounts of Ca 2+ from the sarcoplasmic reticulum (SR), a process te...

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“…RyR2 is a tetrameric SR Ca 2ϩ channel that represents the dominant Ca 2ϩ -release channel in cardiomyocytes. 119,120 Kinetics of RyR2 channel opening is complex, with the open probability state being stabilized by several factors including cytosolic Ca 2ϩ , cyclic ADP-ribose (cADPR), caffeine, and phosphorylation by several protein kinases including PKA and Ca 2ϩ /calmodulindependent protein kinase II (CaMKII). 121,122 The closed state of RyR2 is stabilized by binding of 4 subunits of the Ϸ12-kDa FK506-binding protein FKBP12.…”

Section: Pde4d-ryr2 Interactionmentioning

confidence: 99%

cAMP-Specific Phosphodiesterase-4 Enzymes in the Cardiovascular System

Houslay

Baillie

Maurice

2007

Circulation Research

278

170

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Abstract-Cyclic AMP regulates a vast number of distinct events in all cells. Early studies established that its hydrolysisby cyclic nucleotide phosphodiesterases (PDEs) controlled both the magnitude and the duration of its influence. Recent evidence shows that PDEs also act as coincident detectors linking cyclic-nucleotide-and non-cyclic-nucleotide-based cellular signaling processes and are tethered with great selectively to defined intracellular structures, thereby integrating and spatially restricting their cellular effects in time and space. Although 11 distinct families of PDEs have been defined, and cells invariably express numerous individual PDE enzymes, a large measure of our increased appreciation of the roles of these enzymes in regulating cyclic nucleotide signaling has come from studies on the PDE4 family. Four PDE4 genes encode more than 20 isoforms. Alternative mRNA splicing and the use of different promoters allows cells the possibility of expressing numerous PDE4 enzymes, each with unique amino-terminal-targeting and/or regulatory sequences. Dominant negative and small interfering RNA-mediated knockdown strategies have proven that particular isoforms can uniquely control specific cellular functions. Thus the protein kinase A phosphorylation status of the ␤ 2 adrenoceptor and, thereby, its ability to switch its signaling to extracellular signal-regulated kinase activation, is uniquely regulated by PDE4D5 in cardiomyocytes. We describe how cardiomyocytes and vascular smooth muscle cells selectively vary both the expression and the catalytic activities of PDE4 isoforms to regulate their various functions and how altered regulation of these processes can influence the development, or resolution, of cardiovascular pathologies, such as heart failure, as well as various vasculopathies. (Circ Res. 2007;100:950-966.)

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Calcium Biology of the Transverse Tubules in Heart

Cited by 56 publications

References 50 publications

Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin 43 containing gap junctions in cardiac Myocytes

Vinculin directly binds zonula occludens-1 and is essential for stabilizing connexin 43 containing gap junctions in cardiac Myocytes

Excitation-contraction coupling and mitochondrial energetics

cAMP-Specific Phosphodiesterase-4 Enzymes in the Cardiovascular System

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