Increasing SERCA function promotes initiation of calcium sparks and breakup of calcium waves

2021 ◽  
Author(s):  
Daisuke Sato ◽  
Hitoshi Uchimoumi ◽  
Donald M. Bers
Keyword(s):  
Calcium Waves ◽  
Calcium Sparks

scholarly journals Ryanodine receptor gating controls generation of diastolic calcium waves in cardiac myocytes

2015 ◽  
Vol 145 (6) ◽  
pp. 489-511 ◽  
Author(s):  
Pavol Petrovič ◽  
Ivan Valent ◽  
Elena Cocherová ◽  
Jana Pavelková ◽  
Alexandra Zahradníková
Keyword(s):  
Ryanodine Receptor ◽  
Calcium Sensitivity ◽  
Cytosolic Calcium ◽  
Calcium Waves ◽  
Calcium Sparks ◽  
Calcium Spark ◽  
Gating Model ◽  
Calcium Diffusion ◽  
Confocal Scanning ◽  
Deterministic Description

The role of cardiac ryanodine receptor (RyR) gating in the initiation and propagation of calcium waves was investigated using a mathematical model comprising a stochastic description of RyR gating and a deterministic description of calcium diffusion and sequestration. We used a one-dimensional array of equidistantly spaced RyR clusters, representing the confocal scanning line, to simulate the formation of calcium sparks. Our model provided an excellent description of the calcium dependence of the frequency of diastolic calcium sparks and of the increased tendency for the production of calcium waves after a decrease in cytosolic calcium buffering. We developed a hypothesis relating changes in the propensity to form calcium waves to changes of RyR gating and tested it by simulation. With a realistic RyR gating model, increased ability of RyR to be activated by Ca2+ strongly increased the propensity for generation of calcium waves at low (0.05–0.1-µM) calcium concentrations but only slightly at high (0.2–0.4-µM) calcium concentrations. Changes in RyR gating altered calcium wave formation by changing the calcium sensitivity of spontaneous calcium spark activation and/or the average number of open RyRs in spontaneous calcium sparks. Gating changes that did not affect RyR activation by Ca2+ had only a weak effect on the propensity to form calcium waves, even if they strongly increased calcium spark frequency. Calcium waves induced by modulating the properties of the RyR activation site could be suppressed by inhibiting the spontaneous opening of the RyR. These data can explain the increased tendency for production of calcium waves under conditions when RyR gating is altered in cardiac diseases.

scholarly journals Evolution of Cardiac Calcium Waves from Stochastic Calcium Sparks

2001 ◽  
Vol 80 (1) ◽  
pp. 103-120 ◽  
Author(s):  
Leighton T. Izu ◽  
W. Gil Wier ◽  
C. William Balke
Keyword(s):  
Calcium Waves ◽  
Calcium Sparks

CaMKII as a therapeutic target in catecholaminergic polymorphic ventricular tachycardia type 1

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
M Sadredini ◽  
R Manotheepan ◽  
M Haugsten Hansen ◽  
M Frisk ◽  
WE Louch ◽  
...  
Keyword(s):  
Ventricular Tachycardia ◽  
Therapeutic Target ◽  
Calcium Release ◽  
Left Ventricular ◽  
Catecholaminergic Polymorphic Ventricular Tachycardia ◽  
Polymorphic Ventricular Tachycardia ◽  
Calcium Waves ◽  
Calcium Sparks ◽  
Acetyl Cysteine

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): South-Eastern Norway Regional Health Authority Background In catecholaminergic polymorphic ventricular tachycardia type 1 (CPVT1) adrenergic activation of the cardiac ryanodine receptor (RyR2) causes spontaneous calcium release and triggers arrhythmias. Calcium/calmodulin-dependent protein kinase II (CaMKII) can contribute to such arrhythmogenic calcium release and has been proposed as a therapeutic target in CPVT1. To predict the efficacy and safety of this strategy, it is necessary to know whether the mechanism for CaMKII activation is important for its arrhythmogenic effects, and if inhibition has proarrhythmic effects. We tested (1) if oxidation of CaMKII contributes to spontaneous calcium release in CPVT1 and (2) if inhibition of CaMKII in this condition can induce calcium alternans. Methods Mice with the CPVT1-causative mutation RyR2-R2474S (RyR2-RS) were crossed with mice with the CaMKII M281/282V (MMVV) mutation that prevents CaMKII M281/282 oxidation, to create double mutants (RyR2-RSxMMVV). Telemetric ECG surveillance was used to study in vivo arrhythmias following an adrenergic challenge by i.p. administration of the beta-adrenoceptor agonist isoprenaline. Confocal line-scan imaging and whole-cell calcium imaging were used to study arrhythmogenic calcium release in isolated left ventricular cardiomyocytes during stimulation with isoprenaline. Results As expected, RyR2-RS mice exhibited more arrhythmic events and spontaneous calcium release (i.e. calcium sparks and calcium waves) compared to wild-type mice. Treatment of RyR2-RS cardiomyocytes with either the CaMKII inhibitor KN-93 or the antioxidant n-acetyl-cysteine reduced spontaneous calcium release (i.e. calcium sparks and calcium waves, for KN-93 and n-acetyl-cysteine, respectively). Interestingly, CaMKII inhibition by KN-93 also increased both incidence and degree of arrhythmogenic calcium alternans in RyR2-RS cardiomyocytes. This adverse effect was a result of prolonged refractoriness of calcium release. Furthermore, to test whether the protective effect of antioxidant treatment in RyR2-RS was mediated via CaMKII oxidation, we compared arrhythmias and spontaneous calcium release (i.e. calcium waves) in RyR2-RSxMMVV with RyR2-RS. However, these two genotypes did not differ in either incidence or severity of arrhythmias, and showed similar degree of spontaneous calcium release. Conclusions Inhibition of CaMKII protects against spontaneous calcium release in CPVT1, and is a promising therapeutic strategy. However, the fact that such inhibition also induces calcium alternans needs further exploration. Antioxidative agents also attenuate arrhythmogenic calcium release in CPVT1 cardiomyocytes, but this effect does not seem to involve the M281/282 CaMKII oxidation site. Future studies should explore other oxidation sites.

scholarly journals Oscillatory cytosolic calcium waves independent of stimulated inositol 1,4,5-trisphosphate formation in hepatocytes

1991 ◽  
Vol 266 (19) ◽  
pp. 12272-12282 ◽  
Author(s):  
T.A. Rooney ◽  
D.C. Renard ◽  
E.J. Sass ◽  
A.P. Thomas
Keyword(s):  
Cytosolic Calcium ◽  
Calcium Waves ◽  
Inositol 1,4,5 Trisphosphate

Treatment with beta-blockers normalizes RyR2 phosphorylation and calcium spark activity in atrial myocytes from patients with atrial fibrillation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
V Jimenez-Sabado ◽  
S Casabella ◽  
P Izquierdo ◽  
C Tarifa ◽  
A Llach ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Calcium Imaging ◽  
Adrenergic Receptors ◽  
Beta Blockers ◽  
Funding Source ◽  
Atrial Myocytes ◽  
Calcium Sparks ◽  
Beta Adrenergic ◽  
Calcium Spark ◽  
Confocal Calcium Imaging

Abstract Background Atrial fibrillation has been associated with an increase in ryanodine receptor (RyR2) phosphorylation and local calcium release (calcium sparks). Carvedilol, a nonselective beta-adrenergic receptor blocker also inhibits the cardiac ryanodine receptor (RyR2), but it has been suggested that the enantiomer R-carvedilol only inhibits RyR2 activity and hence has the potential to inhibit calcium sparks without affecting RyR2 phosphorylation. Purpose This study aimed to determine the ability of the enantiomers R- and S-carvedilol to reverse RyR2 phosphorylation at s2808 and calcium sparks induced by the β2-adrenergic agonist fenoterol, in order to determine the relationship between RyR2 phosphorylation at s2808 and calcium spark frequency, and to assess the efficacy of R- and S-carvedilol. Methods Human right atrial myocytes were isolated and subjected to immunofluorescent labelling of total and s2808 phosphorylated RyR2, or loaded with fluo-4 and subjected to confocal calcium imaging. Beta-adrenergic receptors were first activated with 3μM fenoterol and then inhibited by different concentrations of carvedilol R- or S-enantiomers. Results Incubation of myocytes with fenoterol increased the s2808/RyR2 ratio from 0.32±0.03 to 0.66±0.05 (n=18, p<0.001). Incubation with 0.1, 0.3, 1 or 3μM R-carvedilol in the presence of fenoterol changed the s2808/RyR2 ratio to 0.64±0.05, 0.44±0.04, 0.34±0.07 and 0.28±0.05 (p<0.01) respectively. For comparison 3μM S-carvedilol reduced the s2808/RyR2 ratio to 0.23±0.06 in myocytes from 5 patients (p<0.01). Confocal calcium imaging revealed that fenoterol increased the spark density from 0.28±0.04 to 1.24±0.25 events/s/1000μm2 (n=9, p<0.01) and addition of 0.1, 0.3, or 1μM R-carvedilol changed the frequency to 1.32±0.52, 0.38±0.05, and 0.15±0.05 events/s/1000μm2 (p<0.01) respectively. Analysis of atrial myocytes from patients without atrial fibrillation revealed that the s2808/RyR2 ratio was similar in 25 patients treated with beta-blockers (0.39±0.04) and 57 that did not receive beta-blockers (0.44±0.03, p=0.33) while the s2808/RyR2 ratio was significantly smaller in 16 patients with atrial fibrillation receiving beta-blockers (0.43±0.08) than in 5 patients that did not (0.80±0.19, p<0.05). Conclusions R-carvedilol reverses the effects of beta-adrenergic stimulation on s2808 phosphorylation and calcium sparks in human atrial myocytes, and treatment with beta-blockers reduces excessive RyR2 phosphorylation at s2808 in patients with atrial fibrillation to levels observed in those without the arrhythmia, pointing to beta-adrenergic receptors as a target for controlling RyR2 phophorylation and activity in atrial fibrillation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Spanish Ministry of Science and Innovation & Spanish Ministry of Health and Consume

scholarly journals Amplitude Distribution of Calcium Sparks in Confocal Images: Theory and Studies with an Automatic Detection Method

1999 ◽  
Vol 76 (2) ◽  
pp. 606-617 ◽  
Author(s):  
Heping Cheng ◽  
Long-Sheng Song ◽  
Natalia Shirokova ◽  
Adom González ◽  
Edward G. Lakatta ◽  
...  
Keyword(s):  
Detection Method ◽  
Automatic Detection ◽  
Amplitude Distribution ◽  
Calcium Sparks ◽  
Confocal Images
Sign in / Sign up

Export Citation Format

Share Document