Muscarinic Stimulation Facilitates Sarcoplasmic Reticulum Ca Release by Modulating Ryanodine Receptor 2 Phosphorylation Through Protein Kinase G and Ca/Calmodulin-Dependent Protein Kinase II

Ho, Hsiang Ting; Belevych, Andriy E.; Liu, Bin; Bonilla, Ingrid M.; Radwański, Przemysław; Кубасов, И. В.; Valdivia, Héctor H.; Schober, Karsten E.; Carnes, Cynthia A.; Györke, Sándor

doi:10.1161/hypertensionaha.116.07666

Cited by 25 publications

(27 citation statements)

References 72 publications

(87 reference statements)

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“…For calcium waves to occur a mechanism is required to maintain SR calcium content above threshold (Venetucci et al, 2007 ; Ho et al, 2016 ). SERCA function increases in paroxysmal AF (Xie et al, 2012 ; Voigt et al, 2014 ) which would explain how SR calcium content could be maintained in spite of an increase in RyR mediated calcium leak.…”

Section: The Pathophysiology Of Atrial Fibrillationmentioning

confidence: 99%

Calcium in the Pathophysiology of Atrial Fibrillation and Heart Failure

et al. 2018

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Atrial fibrillation (AF) is commonly associated with heart failure. A bidirectional relationship exists between the two—AF exacerbates heart failure causing a significant increase in heart failure symptoms, admissions to hospital and cardiovascular death, while pathological remodeling of the atria as a result of heart failure increases the risk of AF. A comprehensive understanding of the pathophysiology of AF is essential if we are to break this vicious circle. In this review, the latest evidence will be presented showing a fundamental role for calcium in both the induction and maintenance of AF. After outlining atrial electrophysiology and calcium handling, the role of calcium-dependent afterdepolarizations and atrial repolarization alternans in triggering AF will be considered. The atrial response to rapid stimulation will be discussed, including the short-term protection from calcium overload in the form of calcium signaling silencing and the eventual progression to diastolic calcium leak causing afterdepolarizations and the development of an electrical substrate that perpetuates AF. The role of calcium in the bidirectional relationship between heart failure and AF will then be covered. The effects of heart failure on atrial calcium handling that promote AF will be reviewed, including effects on both atrial myocytes and the pulmonary veins, before the aspects of AF which exacerbate heart failure are discussed. Finally, the limitations of human and animal studies will be explored allowing contextualization of what are sometimes discordant results.

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Section: The Pathophysiology Of Atrial Fibrillationmentioning

confidence: 99%

Calcium in the Pathophysiology of Atrial Fibrillation and Heart Failure

et al. 2018

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“…It is well described that short-term β-adrenergic stimulation increases glucose uptake and oxidation (Morisco et al, 2005 ; Nagoshi et al, 2011 ). Stimulation by the use of an agonist (epinephrine) can also favor Ca 2+ handling cycle, with potential beneficial in myocardial contractility (Collins-Nakai et al, 1994 ; Briston et al, 2014 ; Grimm et al, 2015 ; Ho et al, 2016 ). Moreover, recent study demonstrated that a selective β3-adrenergic receptor agonist (BRL 37344 ) favors left ventricular relaxation in Langendorff-perfused rat hearts via the NO/cGMP/PKG axis, thus by activating specific redox signaling and favoring beneficial adaptive process (Angelone et al, 2008 ; Cannavo and Koch, 2017 ).…”

Section: Discussion: Therapeutic Strategiesmentioning

confidence: 99%

Dioxygen and Metabolism; Dangerous Liaisons in Cardiac Function and Disease

Angelini

Xie

2017

Front. Physiol.

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The heart must consume a significant amount of energy to sustain its contractile activity. Although the fuel demands are huge, the stock remains very low. Thus, in order to supply its daily needs, the heart must have amazing adaptive abilities, which are dependent on dioxygen availability. However, in myriad cardiovascular diseases, “fuel” depletion and hypoxia are common features, leading cardiomyocytes to favor low-dioxygen-consuming glycolysis rather than oxidation of fatty acids. This metabolic switch makes it challenging to distinguish causes from consequences in cardiac pathologies. Finally, despite the progress achieved in the past few decades, medical treatments have not improved substantially, either. In such a situation, it seems clear that much remains to be learned about cardiac diseases. Therefore, in this review, we will discuss how reconciling dioxygen availability and cardiac metabolic adaptations may contribute to develop full and innovative strategies from bench to bedside.

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“…This effect would counteract the negative inotropic action of HS, which would have been greater in the absence of RyR2 phosphorylation. Supporting this concept, Ho et al (13) recently demonstrated that cholinergic stimulation of the heart produced an increase in SR Ca 2ϩ release at low SR Ca 2ϩ content compared with nonstimulated hearts. The consequent enhancement of FCaR, which occurs without alterations of I Ca , is due to a facilitation of SR Ca 2ϩ release produced by PKG-dependent phosphorylation of RyR2 at the Ser 2808 site.…”

Section: New and Noteworthy Increasing Ryanodine Receptor (Ryr)2mentioning

confidence: 93%

Impact of RyR2 potentiation on myocardial function

Lascano

Negroni

Petroff

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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This perspective attempts to shed light on an old and not yet solved controversy in cardiac physiology, i.e., the impact of increasing ryanodine receptor (RyR)2 open probability on myocardial function. Based on an already proven myocyte model, it was shown that increasing RyR2 open probability results in a purely short-lived increase in Ca transient amplitude, and, therefore, it does not increase cardiac contractility. However, potentiation of RyR2 activity permanently enhances fractional Ca release, shifting the intracellular Ca transient versus sarcoplasmic reticulum (SR) Ca content curve to a new state of higher efficiency. This would allow the heart to maintain a given contractility despite a decrease in SR Ca content, to enhance contractility if SR Ca content is simultaneously preserved or to successfully counteract the effects of a negative inotropic intervention. Increasing ryanodine receptor (RyR)2 open probability does not increase cardiac contractility. However, RyR2 potentiation shifts the intracellular Ca transient-sarcoplasmic reticulum (SR) Ca content relationship toward an enhanced efficiency state, which may contribute to a positive inotropic effect, preserve contractility despite decreased SR Ca content, or successfully counteract the effects of a negative inotropic action.

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Muscarinic Stimulation Facilitates Sarcoplasmic Reticulum Ca Release by Modulating Ryanodine Receptor 2 Phosphorylation Through Protein Kinase G and Ca/Calmodulin-Dependent Protein Kinase II

Cited by 25 publications

References 72 publications

Calcium in the Pathophysiology of Atrial Fibrillation and Heart Failure

Calcium in the Pathophysiology of Atrial Fibrillation and Heart Failure

Dioxygen and Metabolism; Dangerous Liaisons in Cardiac Function and Disease

Impact of RyR2 potentiation on myocardial function

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