Cardiac Excitation–Contraction Coupling

Bers, Donald M.; Despa, Sanda

doi:10.1016/b978-0-12-378630-2.00221-8

Cited by 258 publications

(308 citation statements)

References 8 publications

Supporting

Mentioning

293

Contrasting

Unclassified

Order By: Relevance

“…through L-type Ca 2+ channel and NCX (sodium-calcium exchanger)). 16 Although ryanodine receptors (RyRs) are the major cardiac SR/ER Ca 2+ -release channels involved in excitation-contraction coupling (ECC) 17 and ischemia-reperfusion (IR) injury, 18 recent studies reported an increasing role for inositol 1,4,5-trisphosphate receptors (IP 3 Rs) Ca 2+ -release channels in the modulation of ECC and cell death. 19,20 Ca 2+ -handling proteins of ER and mitochondria are highly concentrated at mitochondria-associated ER membranes (MAMs), providing a direct and proper mitochondrial Ca 2+ signaling, including VDAC, Grp75 and IP 3 R1.…”

mentioning

confidence: 99%

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

Gomez¹,

Thiebaut²,

Paillard³

et al. 2015

Cell Death Differ

105

View full text Add to dashboard Cite

Glycogen synthase kinase-3β (GSK3β) is a multifunctional kinase whose inhibition is known to limit myocardial ischemiareperfusion injury. However, the mechanism mediating this beneficial effect still remains unclear. Mitochondria and sarco/ endoplasmic reticulum (SR/ER) are key players in cell death signaling. Their involvement in myocardial ischemia-reperfusion injury has gained recognition recently, but the underlying mechanisms are not yet well understood. We questioned here whether GSK3β might have a role in the Ca 2+ transfer from SR/ER to mitochondria at reperfusion. We showed that a fraction of GSK3β protein is localized to the SR/ER and mitochondria-associated ER membranes (MAMs) in the heart, and that GSK3β specifically interacted with the inositol 1,4,5-trisphosphate receptors (IP 3 Rs) Ca 2+ channeling complex in MAMs. We demonstrated that both pharmacological and genetic inhibition of GSK3β decreased protein interaction of IP 3 R with the Ca 2+ channeling complex, impaired SR/ER Ca 2+ release and reduced the histamine-stimulated Ca 2+ exchange between SR/ER and mitochondria in cardiomyocytes. During hypoxia reoxygenation, cell death is associated with an increase of GSK3β activity and IP 3 R phosphorylation, which leads to enhanced transfer of Ca 2+ from SR/ER to mitochondria. Inhibition of GSK3β at reperfusion reduced both IP 3 R phosphorylation and SR/ER Ca 2+ release, which consequently diminished both cytosolic and mitochondrial Ca 2+ concentrations, as well as sensitivity to apoptosis. We conclude that inhibition of GSK3β at reperfusion diminishes Ca 2+ leak from IP 3 R at MAMs in the heart, which limits both cytosolic and mitochondrial Ca 2+ overload and subsequent cell death. Glycogen synthase kinase-3 (GSK3) was originally identified as a phosphorylating kinase for glycogen synthase. 1,2 It has two isoforms, α and β, that possess strong homology in their kinase domains with, however, distinct functions. 3 GSK3 is constitutively active but it can be inhibited by phosphorylation on serine 21 (Ser21) for GSK3α and Ser9 for GSK3β. 4 In the heart, GSK3β has several important roles in cardiac hypertrophy 5 and ischemia-reperfusion (IR) injury. 6 Accumulating evidence indicates that phospho-Ser9-GSK3β-mediated cytoprotection is achieved by an increased threshold for permeability transition pore (PTP) opening. [6][7][8][9] The mechanism by which GSK3β delays PTP opening still remains unclear. It has been reported that GSK3β could interact with ANT at the inner mitochondrial membrane in the heart 9 and/or to phosphorylate voltage-dependent anion channel (VDAC) and cyclophilin D (CypD) in cancer cells. 10,11 GSK3β also has other proposed mechanisms of action, including a poorly characterized role in calcium (Ca 2+ ) homeostasis regulation 12 and protein-protein interactions, 9 as well as functions in different subcellular fractions such as the nucleus, cytosol and mitochondria. 13 Reperfusion is the most powerful intervention to salvage ischemic myocardium. However, it can also paradoxically lead to ca...

show abstract

mentioning

confidence: 99%

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

Gomez¹,

Thiebaut²,

Paillard³

et al. 2015

Cell Death Differ

105

View full text Add to dashboard Cite

show abstract

“…This is achieved primarily by cAMPdependent protein kinase (PKA)-mediated phosphorylation of several proteins involved in calcium handling and excitationcontraction coupling such as L-type calcium channels, ryanodine receptors, troponin I and phospholamban (PLN) 4 . PLN is a small protein regulator of the cardiac sarcoplasmic/endoplasmic reticulum (SR) calcium ATPase 2a (SERCA2a), and upon PKAdependent phosphorylation, the PLN-mediated SERCA2a inhibition is relieved, leading to an increased diastolic SR calcium reuptake 5 .…”

mentioning

confidence: 99%

In vivo model with targeted cAMP biosensor reveals changes in receptor–microdomain communication in cardiac disease

et al. 2015

View full text Add to dashboard Cite

3 0 ,5 0 -cyclic adenosine monophosphate (cAMP) is an ubiquitous second messenger that regulates physiological functions by acting in distinct subcellular microdomains. Although several targeted cAMP biosensors are developed and used in single cells, it is unclear whether such biosensors can be successfully applied in vivo, especially in the context of disease. Here, we describe a transgenic mouse model expressing a targeted cAMP sensor and analyse microdomain-specific second messenger dynamics in the vicinity of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). We demonstrate the biocompatibility of this targeted sensor and its potential for real-time monitoring of compartmentalized cAMP signalling in adult cardiomyocytes isolated from a healthy mouse heart and from an in vivo cardiac disease model. In particular, we uncover the existence of a phosphodiesterase-dependent receptor-microdomain communication, which is affected in hypertrophy, resulting in reduced b-adrenergic receptor-cAMP signalling to SERCA.

show abstract

“…In brief, during each cycle, depolarization of the membrane causes an influx of Ca 2+ into the cytoplasm through the sequential opening of L-type Ca 2+ channels. 32 This local increase in calcium concentration close to the channel is sufficient to activate the release of calcium through the ryanodine receptor from the SR. The coupling of ryanodine receptor activity to L-type Ca 2+ channels gating is structurally based on their clustering in small cellular compartments.…”

Section: Developments In Vehicles and Gene Delivery Techniques For Mymentioning

confidence: 99%

Sarcoplasmic reticulum and calcium cycling targeting by gene therapy

Hulot

Senyei

2012

Gene Ther

View full text Add to dashboard Cite

Although progress in conventional treatments is making steady and incremental gains to reduce mortality associated with heart failure (HF), there remains a need to explore potentially new therapeutic approaches. HF induced by different etiologies such as coronary artery disease, hypertension, diabetes, infection or inflammation results generally in calcium cycling dysregulation at the myocyte level. Recent advances in understanding of the molecular basis of these calcium cycling abnormalities, together with the evolution of increasingly efficient gene transfer technology, has placed HF within the reach of gene-based therapy. Furthermore, the recent successful completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium pump ushers in a new era for gene therapy for the treatment of HF.

show abstract

Cardiac Excitation–Contraction Coupling

Cited by 258 publications

References 8 publications

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

The SR/ER-mitochondria calcium crosstalk is regulated by GSK3β during reperfusion injury

In vivo model with targeted cAMP biosensor reveals changes in receptor–microdomain communication in cardiac disease

Sarcoplasmic reticulum and calcium cycling targeting by gene therapy

Contact Info

Product

Resources

About