The effects of low concentrations of caffeine on spontaneous Ca release in isolated rat ventricular myocytes

Trafford, Andrew W.; Sibbring, Gillian C.; Díaz, M. E.; Eisner, David

doi:10.1054/ceca.2000.0156

Cited by 92 publications

(87 citation statements)

References 33 publications

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“…23 This can occur either by an increase of SR content or by decreasing the threshold SR Ca 2ϩ content by affecting the properties of the RyR. 24,34 In agreement with previous work, 16 we found that when caffeine was applied under control conditions, Ca 2ϩ waves were not seen in the steady state. In a fraction of cells, Ca 2ϩ waves were seen immediately after caffeine application.…”

Section: Discussionsupporting

confidence: 90%

“…Previous work has shown that in resting cells waves occur when SR Ca 2ϩ content reaches a threshold 22,23 and that caffeine reduces this threshold and SR content. 24 In addition isoproterenol can increase SR Ca 2ϩ content. 25,26 We therefore hypothesized that caffeine in isolation reduces both SR Ca 2ϩ content and threshold for waves, so the SR content falls below the threshold for Ca 2ϩ waves.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Increasing Ryanodine Receptor Open Probability Alone Does Not Produce Arrhythmogenic Calcium Waves

Venetucci

Trafford

Eisner

2007

Circulation Research

176

151

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Abstract-Diastolic waves of Ca 2ϩ release have been shown to activate delayed afterdepolarizations as well as some cardiac arrhythmias. The aim of this study was to investigate whether increasing ryanodine receptor open probability alone or in the presence of ␤-adrenergic stimulation produces diastolic Ca release from the sarcoplasmic reticulum (SR). When voltage-clamped rat ventricular myocytes were exposed to caffeine (0.5 to 1.0 mmol), diastolic Ca 2ϩ release was seen to accompany the first few stimuli but was never observed in the steady state. We attribute the initial phase of diastolic Ca 2ϩ release to a decrease in the threshold SR Ca 2ϩ content required to activate Ca 2ϩ waves and its subsequent disappearance to a decrease of SR content below this threshold. Application of isoproterenol (1 mol

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Increasing Ryanodine Receptor Open Probability Alone Does Not Produce Arrhythmogenic Calcium Waves

Venetucci

Trafford

Eisner

2007

Circulation Research

176

151

View full text Add to dashboard Cite

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“…They also demonstrated that generation of spontaneous Ca waves and sparks in HF myocytes occurs at abnormally low intra-SR Ca levels, thereby accounting for, or contributing to, the reduced sequestration of Ca in the SR in HF myocytes. The increased occurrence of spontaneous release events at reduced SR Ca content in HF myocytes is reminiscent of the effects of the RyR-sensitizing agent caffeine (11,25) and consistent with potential changes in the functional activity of RyRs in failing hearts.…”

Section: Intra-sr [Ca]supporting

confidence: 56%

Abnormal intrastore calcium signaling in chronic heart failure

Kubalova¹,

Terentyev²,

Viatchenko‐Karpinski³

et al. 2005

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

182

160

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Diminished Ca release from the sarcoplasmic reticulum (SR) is an important contributor to the impaired contractility of the failing heart. Despite extensive effort, the underlying causes of abnormal SR Ca release in heart failure (HF) remain unknown. We used a combination of simultaneous imaging of cytosolic and SR intralu- excitation-contraction coupling ͉ ryanodine receptor ͉ sarcoplasmic reticulum

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“…Moderate modulation of RyR2 activity has been shown to have no sustained effect on stimulated SR Ca 2ϩ release due to the regulation of RyR2 by luminal Ca 2ϩ , a phenomenon often referred to as "SR auto-regulation" (25), but it does exert a sustained impact on spontaneous Ca 2ϩ release or SOICR (26). Hence, one may be able to study the modulation of RyR2 by examining the SOICR activity, rather than stimulated SR Ca 2ϩ release or Ca 2ϩ -induced Ca 2ϩ release.…”

Section: Ventricular Tachycardia (Vt)mentioning

confidence: 99%

Functional Consequence of Protein Kinase A-dependent Phosphorylation of the Cardiac Ryanodine Receptor

Xiao

Tian

Xie

et al. 2007

Journal of Biological Chemistry

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The phosphorylation of the cardiac Ca 2؉ -release channel (ryanodine receptor, RyR2) by protein kinase A (PKA) has been extensively characterized, but its functional consequence remains poorly defined and controversial. We have previously shown that RyR2 is phosphorylated by PKA at two major sites, serine 2030 and serine 2808, of which Ser-2030 is the major PKA site responding to ␤-adrenergic stimulation. Here we investigated the effect of the phosphorylation of RyR2 by PKA on the properties of single channels and on spontaneous Ca 2؉ release during sarcoplasmic reticulum Ca 2؉ overload, a process we have referred to as store overload-induced Ca 2؉ release (SOICR). We found that PKA activated single RyR2 channels in the presence, but not in the absence, of luminal Ca 2؉ . On the other hand, PKA had no marked effect on the sensitivity of the RyR2 channel to activation by cytosolic Ca 2؉ . Importantly, the S2030A mutation, but not mutations of Ser-2808, diminished the effect of PKA on RyR2. Furthermore, a phosphomimetic mutation, S2030D, potentiated the response of RyR2 to luminal Ca 2؉ and enhanced the propensity for SOICR in HEK293 cells. In intact rat ventricular myocytes, the activation of PKA by isoproterenol reduced the amplitude and increased the frequency of SOICR. Confocal line-scanning fluorescence microscopy further revealed that the activation of PKA by isoproterenol increased the rate of Ca 2؉ release and the propagation velocity of spontaneous Ca 2؉ waves, despite reduced wave amplitude and resting cytosolic Ca 2؉ . Collectively, our data indicate that PKA-dependent phosphorylation enhances the response of RyR2 to luminal Ca 2؉ and reduces the threshold for SOICR and that this effect of PKA is largely mediated by phosphorylation at Ser-2030. Ventricular tachycardia (VT)4 is the leading cause of sudden death, particularly in patients with heart failure (HF), but the molecular mechanisms underlying the high incidence of VT in HF are not completely understood (1). A major cause of VT is believed to be delayed afterdepolarizations, which are produced by spontaneous Ca 2ϩ release from the sarcoplasmic reticulum (SR) via the cardiac ryanodine receptor (RyR2) during SR Ca 2ϩ overload (2-5), a process we referred to as store overload-induced Ca 2ϩ release (SOICR) (6, 7). Physical or emotional stresses, which activate the ␤-adrenergic receptor (AR)/protein kinase A (PKA) signaling pathway, are common triggers for SOICR. Marks' group has shown that RyR2 is phosphorylated by PKA at a single residue, Ser-2808 (10, 11), which was originally identified as a unique Ca 2ϩ -and calmodulin-dependent protein kinase II phosphorylation site (12,13 (23, 24). These results are seemingly inconsistent with those of in vitro studies. The reasons for this apparent discrepancy are unknown.Moderate modulation of RyR2 activity has been shown to have no sustained effect on stimulated SR Ca 2ϩ release due to the regulation of RyR2 by luminal Ca 2ϩ , a phenomenon often referred to as "SR auto-regulation" (25), but it does exert a ...

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The effects of low concentrations of caffeine on spontaneous Ca release in isolated rat ventricular myocytes

Cited by 92 publications

References 33 publications

Increasing Ryanodine Receptor Open Probability Alone Does Not Produce Arrhythmogenic Calcium Waves

Increasing Ryanodine Receptor Open Probability Alone Does Not Produce Arrhythmogenic Calcium Waves

Abnormal intrastore calcium signaling in chronic heart failure

Functional Consequence of Protein Kinase A-dependent Phosphorylation of the Cardiac Ryanodine Receptor

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