Essential role of ryanodine receptor 2 phosphorylation in the effect of azumolene on ventricular arrhythmia vulnerability in a rabbit heart model

Si, Daoyuan; Azam, Muhammad; Lai, Patrick F.H.; Zamiri, Nima; Kichigina, Galina; Asta, John; Massé, Stéphane; Bokhari, Mahmoud; Porta‐Sánchez, Andreu; Labos, Christopher; Sun, Huan; Yang, Ping; Nanthakumar, Kumaraswamy

doi:10.1111/jce.13737

Cited by 13 publications

(18 citation statements)

References 39 publications

(79 reference statements)

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“…Aberrant phosphorylation of RyR2 has been linked to atrial fibrillation (Chiang et al, 2014;Si et al, 2018), heart failure (Dobrev and Wehrens, 2014;Marx et al, 2000;van Oort et al, 2010), increased cell death in ischemia-reperfusion (Di Carlo et al, 2014), cognitive dysfunction (Liu et al, 2012), and Alzheimer's disease (Lacampagne et al, 2017), although the exact molecular mechanisms are heavily disputed (Bers, 2012;Eschenhagen, 2010).…”

Section: Introductionmentioning

confidence: 99%

The Cardiac Ryanodine Receptor Phosphorylation Hotspot Embraces PKA in a Phosphorylation-Dependent Manner

2019

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Ryanodine receptors (RyRs) are intracellular Ca 2+ release channels controlling essential cellular functions. RyRs are targeted by cyclic AMP (cAMP)dependent protein kinase A (PKA), a controversial regulation implicated in disorders ranging from heart failure to Alzheimer's. Using crystal structures, we show that the phosphorylation hotspot domain of RyR2 embraces the PKA catalytic subunit, with an extensive interface not seen in PKA complexes with peptides. We trapped an intermediary open-form PKA bound to the RyR2 domain and an ATP analog, showing that PKA can engage substrates in an open form. Phosphomimetics or prior phosphorylation at nearby sites in RyR2 either enhance or reduce the activity of PKA. Finally, we show that a phosphomimetic at S2813, a well-known target site for calmodulin-dependent kinase II, induces the formation of an alpha helix in the phosphorylation domain, resulting in increased interactions and PKA activity. This shows that the different phosphorylation sites in RyR2 are not independent.

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Section: Introductionmentioning

confidence: 99%

The Cardiac Ryanodine Receptor Phosphorylation Hotspot Embraces PKA in a Phosphorylation-Dependent Manner

2019

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“…In our previous study, which used azumolene, an active analog of dantrolene, we demonstrated that the phosphorylation of RyR2 is essential for azumolene function in ischemia and long-duration ventricular fibrillation. 24 The cardioprotective effect of dantrolene has also been demonstrated in various acute and chronic models of DICM, 29,30 but these previous studies did not assess the impact on calcium dynamics as demonstrated in this study.…”

Section: Dantrolene and Cardiac Contractile Functionmentioning

confidence: 72%

“…For calcium transient duration (CaTD) analysis, 0 to 50% of repolarization (CaTD 50 ) and 0 to 80% of repolarization (CaTD 80 ) were analyzed, as described previously. 23,24 Calcium amplitude alternans ratio analysis Ca 21 amplitude alternans refers to the beat-to-beat difference of Ca 21 signal amplitudes during cardiac stimulation. A calcium amplitude alternans ratio (CaAAR) of 1 indicates similar amplitudes, whereas a ratio of 0.5 refers to a 50% difference between large and small Ca 21 amplitudes.…”

Section: Calcium Transient Duration Analysismentioning

confidence: 99%

“…As described in our previous publications, this parameter was calculated as a ratio (smallest Ca 21 signals)/(largest Ca 21 signals), where the largest and smallest Ca 21 signals were each derived from either odd or even beats. 24,25 Calcium transient rise time analysis Rise time of calcium transient upstrokes (calcium transient [CaT] rise time) was calculated as the time duration for fluorescence to rise from minimum (10%) to maximum (90%) and was expressed in milliseconds. 26 Diastolic/spontaneous calcium leak The presence of spontaneous calcium elevation (SCaE) is the result of a leaky RyR2 receptor during diastole.…”

Section: Calcium Transient Duration Analysismentioning

confidence: 99%

“…The calcium signal fluorescence elevation between the final pacing beat and the first spontaneous beat was calculated as described previously. 24…”

Section: Calcium Transient Duration Analysismentioning

confidence: 99%

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Cardioprotective effects of dantrolene in doxorubicin-induced cardiomyopathy in mice

et al. 2021

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BACKGROUND Doxorubicin (Dox) is a potent chemotherapeutic agent, but its usage is limited by dose-dependent cardiotoxicity. Intracellular calcium dysregulation has been reported to be involved in doxorubicin-induced cardiomyopathy (DICM). The cardioprotective role of RyR stabilizer dantrolene (Dan) on the calcium dynamics of DICM has not yet been explored. OBJECTIVE To evaluate the effects of dantrolene on intracellular calcium dysregulation and cardiac contractile function in a DICM model.METHODS Adult male C57BL/6 mice were randomized into 4 groups: (1) Control, (2) Dox Only, (3) Dan Only, and (4) Dan 1 Dox. Fractional shortening (FS) and left ventricular ejection fraction (LVEF) were assessed by echocardiography. In addition, mice were sacrificed 2 weeks after doxorubicin injection for optical mapping of the heart in a Langendorff setup. RESULTSTreatment with Dox was associated with a reduction in both FS and LVEF at 2 weeks (P , .0001) and 4 weeks (P , .006). Dox treatment was also associated with prolongation of calcium transient durations CaTD 50 (P 5 .0005) and CaTD 80 (P , .0001) and reduction of calcium amplitude alternans ratio (P , .0001). Concomitant treatment with Dan prevented the Dox-induced decline in FS and LVEF (P , .002 at both 2 and 4 weeks). Dan also prevented Dox-induced prolongation of CaTD 50 and CaTD 80 and improved the CaT alternans ratio (P , .0001). Finally, calcium transient rise time was increased in the doxorubicin-treated group, indicating RyR2 dyssynchrony, and dantrolene prevented this prolongation (P 5 .02).CONCLUSION Dantrolene prevents cardiac contractile dysfunction following doxorubicin treatment by mitigating dysregulation of calcium dynamics.

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Effects of azumolene on arrhythmia substrate in a model of recurrent long-duration ventricular fibrillation

Chakraborty

Massé

Azam

et al. 2022

Biochemical and Biophysical Research Communications

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Essential role of ryanodine receptor 2 phosphorylation in the effect of azumolene on ventricular arrhythmia vulnerability in a rabbit heart model

Abstract: Ventricular refibrillation following LDVF was reduced by azumolene, which also improves calcium dynamics. RyR2 phosphorylation at Ser2808 is a prerequisite for the beneficial effects of azumolene.

Cited by 13 publications

References 39 publications

The Cardiac Ryanodine Receptor Phosphorylation Hotspot Embraces PKA in a Phosphorylation-Dependent Manner

The Cardiac Ryanodine Receptor Phosphorylation Hotspot Embraces PKA in a Phosphorylation-Dependent Manner

Cardioprotective effects of dantrolene in doxorubicin-induced cardiomyopathy in mice

Effects of azumolene on arrhythmia substrate in a model of recurrent long-duration ventricular fibrillation

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