Abnormal intrastore calcium signaling in chronic heart failure

Kubalova, Zuzana; Terentyev, Dmitry; Viatchenko‐Karpinski, Serge; Nishijima, Yoshinori; Györke, Inna; Terentyeva, Radmila; Cunha, Daise Nunes Queiroz da; Sridhar, Arun; Feldman, David S.; Hamlin, Robert L.; Carnes, Cynthia A.; Györke, Sándor

doi:10.1073/pnas.0504298102

Cited by 181 publications

(180 citation statements)

References 44 publications

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“…This observation implies that the threshold for SOICR in failing hearts is reduced, which is consistent with the observation that single RyR2 channels isolated from failing canine hearts exhibited an increased sensitivity to luminal Ca 2ϩ (37). Furthermore, we have shown that RyR2 in rats with HF was phosphorylated at Ser-2030 upon Iso injection.…”

Section: Proposed Role For Pka-dependent Phosphorylation Of Ryr2 Insupporting

confidence: 75%

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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Section: Proposed Role For Pka-dependent Phosphorylation Of Ryr2 Insupporting

confidence: 75%

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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“…5D). shows that such a high concentration of caffeine induced a decrease of the SR fluorescence signal in our preparation, similar to previous studies [9,23]. Therefore, the minimal fluorescence value during caffeine application can be used to normalize the SR signal for variable Fluo-5N loading, since the absolute level reached in caffeine mainly depends on the amount of Fluo-5N entrapped in the SR.…”

Section: Reversible Permeabilization With Streptolysin Osupporting

confidence: 51%

“…Recently, it has become increasingly evident that disturbances of this Ca 2+ release mechanism are involved in a wide range of pathologies (e.g. hypertrophy, cardiomyopathies, heart failure, channelopathies of the RyRs [5][6][7][8][9][10][11]). Abnormal and untimely Ca 2+ release from the SR is known to be a key event in precipitating various forms of cardiac arrhythmias.…”

Section: Introductionmentioning

confidence: 99%

Real-time intra-store confocal Ca2+ imaging in isolated mouse cardiomyocytes

Fernández-Tenorio

Niggli

2016

Cell Calcium

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“…Furthermore, it has been suggested that the tonic NO production in the SR may keep RyR in the closed state (34), which has also been observed with some NO donors (35,36). Recently, also in a canine model of heart failure, decreased intra-SR Ca 2ϩ content, associated with increased Ca 2ϩ leak via RyR2, was observed (37). Importantly, these authors found an increased sensitivity of RyR to intraluminal Ca 2ϩ concentrations.…”

Section: Discussionmentioning

confidence: 63%

Deficient ryanodine receptor S -nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytes

González

Beigi

Treuer

et al. 2007

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

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192

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Altered Ca 2؉ homeostasis is a salient feature of heart disease, where the calcium release channel ryanodine receptor (RyR) plays a major role. Accumulating data support the notion that neuronal nitric oxide synthase (NOS1) regulates the cardiac RyR via Snitrosylation. We tested the hypothesis that NOS1 deficiency impairs RyR S-nitrosylation, leading to altered Ca 2؉ homeostasis. Diastolic Ca 2؉ levels are elevated in NOS1 ؊/؊ and NOS1/NOS3 ؊/؊ but not NOS3 ؊/؊ myocytes compared with wild-type (WT), suggesting diastolic Ca 2؉ leakage. Measured leak was increased in NOS1 ؊/؊ and NOS1/NOS3 ؊/؊ but not in NOS3 ؊/؊ myocytes compared with WT. Importantly, NOS1 ؊/؊ and NOS1/NOS3 ؊/؊ myocytes also exhibited spontaneous calcium waves. Whereas the stoichiometry and binding of FK-binding protein 12.6 to RyR and the degree of RyR phosphorylation were not altered in NOS1 ؊/؊ hearts, RyR2 S-nitrosylation was substantially decreased, and the level of thiol oxidation increased. Together, these findings demonstrate that NOS1 deficiency causes RyR2 hyponitrosylation, leading to diastolic Ca 2؉ leak and a proarrhythmic phenotype. NOS1 dysregulation may be a proximate cause of key phenotypes associated with heart disease.heart ͉ nitric oxide ͉ excitation-contraction coupling ͉ oxidative stress ͉ heart failure T he cardiac myocyte has emerged as a prototypic example of the manner in which nitric oxide (NO) signaling occurs in a spatially confined manner. Although neuronal (NOS1) and endothelial (NOS3) isoforms of nitric oxide synthase are located extremely close to one another within the cell on opposite sides of the dyad, they exert opposite effects on myocardial contractility (1). The mechanism(s) for this effect remains controversial. One explanation derived from in vitro observations is that NOS3 inhibits the sarcolemmal L-type calcium channel on the sarcolemmal aspect of the dyad, whereas NOS1 modulates ryanodine receptor (RyR) activity on the sarcoplasmic reticulum (SR) (1-3). Although this paradigm explains many facets of NO activity within the heart, other studies suggest that in the myocyte, NOS1 may bind to and/or regulate other ion channels or effectors, including the plasma membrane calcium/calmodulin-dependent calcium ATPase (4), sarcoplamic reticulum Ca 2ϩ -ATPase (SERCA) (5), and possibly phospholamban (PLB). In addition, there is support for the notion that this effect is mediated by a direct protein posttranslational modification; but again, this assertion is controversial (6).Another facet of NO cardiobiology has emerged that further motivates the importance of understanding the direct NOS effector molecules. In heart failure and/or other states of cardiac injury, NOS1 levels within the heart rise, and NOS1 effectively translocates from the SR to the plasma membrane (2,7,8). Because this phenomenon could have either deleterious effects or adaptive consequences, it is imperative to address definitively the physiologic role of NOS1 in the heart.To address these issues, we tested the hypothesis that the cardiac RyR i...

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Abnormal intrastore calcium signaling in chronic heart failure

Cited by 181 publications

References 44 publications

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

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

Real-time intra-store confocal Ca2+ imaging in isolated mouse cardiomyocytes

Deficient ryanodine receptor S -nitrosylation increases sarcoplasmic reticulum calcium leak and arrhythmogenesis in cardiomyocytes

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