Calmodulin kinase II–mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice

Chelu, Mihail G.; Sarma, Satyam; Sood, Subeena; Wang, Sufen; Oort, Ralph J. van; Skapura, Darlene G.; Li, Na; Santonastasi, Marco; Müller, Frank; Schmitz, Wilhelm; Schotten, Ulrich; Anderson, Mark E.; Valderrábano, Miguel; Dobrev, Dobromir; Wehrens, Xander H.T.

doi:10.1172/jci37059

Cited by 207 publications

(262 citation statements)

References 59 publications

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“…Cardiac homogenates were prepared and probed with antibodies as described previously (42). Bands were quantified using infrared visualization and densitometry (Odyssey).…”

Section: Methodsmentioning

confidence: 99%

Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy

Sarma

Li²,

Oort³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Aberrant intracellular Ca 2+ regulation is believed to contribute to the development of cardiomyopathy in Duchenne muscular dystrophy. Here, we tested whether inhibition of protein kinase A (PKA) phosphorylation of ryanodine receptor type 2 (RyR2) prevents dystrophic cardiomyopathy by reducing SR Ca 2+ leak in the mdx mouse model of Duchenne muscular dystrophy. mdx mice were crossed with RyR2-S2808A mice, in which PKA phosphorylation site S2808 on RyR2 is inactivated by alanine substitution. Compared with mdx mice that developed age-dependent heart failure, mdx-S2808A mice exhibited improved fractional shortening and reduced cardiac dilation. Whereas application of isoproterenol severely depressed cardiac contractility and caused 95% mortality in mdx mice, contractility was preserved with only 19% mortality in mdx-S2808A mice. SR Ca 2+ leak was greater in ventricular myocytes from mdx than mdx-S2808A mice. Myocytes from mdx mice had a higher incidence of isoproterenol-induced diastolic Ca 2+ release events than myocytes from mdx-S2808A mice. Thus, inhibition of PKA phosphorylation of RyR2 reduced SR Ca 2+ leak and attenuated cardiomyopathy in mdx mice, suggesting that enhanced PKA phosphorylation of RyR2 at S2808 contributes to abnormal Ca 2+ homeostasis associated with dystrophic cardiomyopathy.calcium | cardiomyopathy | dystrophin | ryanodine receptor | sarcoplasmic reticulum

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“…Cardiac homogenates were prepared and probed with antibodies as described previously (42). Bands were quantified using infrared visualization and densitometry (Odyssey).…”

Section: Methodsmentioning

confidence: 99%

Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy

Sarma

Li²,

Oort³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…However, other groups have not found PKA-dependent hyperphosphorylation in failing hearts (Xiao et al 2005). In addition, other laboratories suggest that CamKII-dependent phosphorylation of RyR2 is involved in enhanced SR Ca 2þ leak and reduced SR Ca 2þ load in heart failure and may contribute to arrhythmias and contractile dysfunction (Ai et al 2005;Chelu et al 2009;Curran et al 2010;Neef et al 2010). Phosphorylation of other targets of these kinases (troponin I, sarcolemmal Ca 2þ channels, and phospholamban) could also alter the Ca 2þ handling in cardiac and skeletal muscle.…”

Section: Pka and Camkii Phosphorylationmentioning

confidence: 99%

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

Lanner¹,

Georgiou²,

Joshi³

et al. 2010

Cold Spring Harbor Perspectives in Biology

639

543

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Ryanodine receptors (RyRs) are located in the sarcoplasmic/endoplasmic reticulum membrane and are responsible for the release of Ca 2þ from intracellular stores during excitation-contraction coupling in both cardiac and skeletal muscle. RyRs are the largest known ion channels (.2MDa) and exist as three mammalian isoforms (RyR 1 -3), all of which are homotetrameric proteins that interact with and are regulated by phosphorylation, redox modifications, and a variety of small proteins and ions. Most RyR channel modulators interact with the large cytoplasmic domain whereas the carboxy-terminal portion of the protein forms the ion-conducting pore. Mutations in RyR2 are associated with human disorders such as catecholaminergic polymorphic ventricular tachycardia whereas mutations in RyR1 underlie diseases such as central core disease and malignant hyperthermia. This chapter examines the current concepts of the structure, function and regulation of RyRs and assesses the current state of understanding of their roles in associated disorders.

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“…On the other hand, genetic inhibition of RyR2 phosphorylation at S2814 in RyR2-S2814A knockin mice conferred protection against ventricular arrhythmias in mice with heart failure induced by transverse aortic banding [10] . These studies suggest that inhibition of RyR2 phosphorylation by CaMKII might provide a very specifi c way of preventing ventricular and also atrial arrhythmias [6] . Moreover, pharmacological inhibition of the enzyme CaMKII itself might also provide protection against arrhythmias [6,70,71] .…”

Section: Wwwnaturecom/aps Mccauley MD Et Almentioning

confidence: 90%

“…These studies suggest that inhibition of RyR2 phosphorylation by CaMKII might provide a very specifi c way of preventing ventricular and also atrial arrhythmias [6] . Moreover, pharmacological inhibition of the enzyme CaMKII itself might also provide protection against arrhythmias [6,70,71] .…”

Section: Wwwnaturecom/aps Mccauley MD Et Almentioning

confidence: 90%

“…There is now considerable evidence that abnormal RyR2-mediated Ca 2+ release from the SR can lead to both atrial [6,7] and ventricular arrhythmias associated with sudden cardiac death [8][9][10] . Increased SR Ca 2+ release during diastole can lead to activation of the Na + /Ca 2+ -exchanger [11] , which in turn generates a transient inward current that can cause afterdepolarizations and triggered action potentials.…”

Section: Introductionmentioning

confidence: 99%

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Targeting ryanodine receptors for anti-arrhythmic therapy

McCauley

Wehrens

2011

Acta Pharmacol Sin

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Antiarrhythmic drugs are a group of pharmaceuticals that suppress or prevent abnormal heart rhythms, which are often associated with substantial morbidity and mortality. Current antiarrhythmic drugs that typically target plasma membrane ion channels have limited clinical success and in some cases have been described as being pro-arrhythmic. However, recent studies suggest that pathological release of calcium (Ca 2+ ) from the sarcoplasmic reticulum via cardiac ryanodine receptors (RyR2) could represent a promising target for antiarrhythmic therapy. Diastolic SR Ca 2+ release has been linked to arrhythmogenesis in both the inherited arrhythmia syndrome 'catecholaminergic polymorphic ventricular tachycardia' and acquired forms of heart disease (eg, atrial fi brillation, heart failure). Several classes of pharmaceuticals have been shown to reduce abnormal RyR2 activity and may confer protection against triggered arrhythmias through reduction of SR Ca 2+ leak. In this review, we will evaluate the current pharmacological methods for stabilizing RyR2 and suggest treatment modalities based on current evidence of molecular mechanisms.

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Calmodulin kinase II–mediated sarcoplasmic reticulum Ca2+ leak promotes atrial fibrillation in mice

Cited by 207 publications

References 59 publications

Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy

Genetic inhibition of PKA phosphorylation of RyR2 prevents dystrophic cardiomyopathy

Ryanodine Receptors: Structure, Expression, Molecular Details, and Function in Calcium Release

Targeting ryanodine receptors for anti-arrhythmic therapy

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