Intra‐sarcoplasmic reticulum Ca<sup>2+</sup> oscillations are driven by dynamic regulation of ryanodine receptor function by luminal Ca<sup>2+</sup> in cardiomyocytes

Stevens, Sarah; Terentyev, Dmitry; Kalyanasundaram, Anuradha; Periasamy, Muthu; Györke, Sándor

doi:10.1113/jphysiol.2009.175547

Cited by 46 publications

(70 citation statements)

References 41 publications

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“…This sensitivity of the stochastic dynamics of Ca 2ϩ release to the rate of Ca 2ϩ inactivation is consistent with results obtained using Ca 2ϩ -release site models that do not account for Ca 2ϩ homeostasis (18). However, the significance of these observations is unclear given recent experimental results showing that, at even 50 M myoplasmic [Ca 2ϩ ], inactivation is unable to suppress SR Ca 2ϩ release in permeabilized myocytes (45). While the simulated spark duration histograms shown in Fig.…”

supporting

confidence: 88%

Spontaneous Ca²⁺ sparks and Ca²⁺ homeostasis in a minimal model of permeabilized ventricular myocytes

Hartman

Sobie

Smith

2010

American Journal of Physiology-Heart and Circulatory Physiology

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] in the myoplasm or SR can influence the frequency, amplitude, and kinetics of local events. In ventricular myocytes, for instance, propagating Ca 2ϩ waves emerge when spontaneous Ca 2ϩ sparks trigger additional sparks in a regenerative fashion (5). Similarly, changes in channel gating at the level of individual RyRs can immediately affect the production of local events and, over time, influence bulk myoplasmic and SR [Ca 2ϩ ]. An increase in RyR opening will cause a gradual decrease in SR [Ca 2ϩ ] (46), whereas inhibition of RyR opening, over time, will lead to elevated SR [Ca 2ϩ ] (21). This principle has been elegantly demonstrated by Lukyanenko and coworkers (35) in quiescent rat ventricular myocytes treated with caffeine (to sensitize RyRs) or tetracaine (to inhibit RyRs).In heart cells, changes in Ca 2ϩ signaling due to altered RyR activity are currently receiving considerable attention because of close links to disease (13, 48). In particular, catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited disorder associated with a dramatic increase in arrhythmia risk, results from mutations in either RyRs or calsequestrin, a SR Ca 2ϩ buffer protein that associates with and modulates RyRs (20,33). Experiments in vitro have shown that CPVT-causing mutations usually increase the open probability of the RyR, resulting in a hyperactive or "leaky" channel (12,28,31). Studies (1, 36) have also suggested that leaky RyRs are characteristic of several experimental heart failure models. Thus, a quantitative understanding of how changes in RyR gating influence local and global Ca 2ϩ responses can provide insights into disease pathophysiology and can potentially suggest novel therapies.The difference in spatial scales between local and global Ca 2ϩ signals, however, creates significant challenges for the development of mechanistic mathematical models. In particular, gating of RyRs depends on both myoplasmic and SR [Ca 2ϩ ] (30), and concentrations within clusters during local events can be dramatically different from the bulk concentrations. In addition, because of the relatively small number of RyRs responsible for Ca 2ϩ sparks (6), the stochastic gating of these channels must be considered when simulating local events. Previous studies (9,27,42,44) have used Monte Carlo simulation methods to investigate the stochastic triggering of Ca 2ϩ sparks, but these have generally treated myoplasmic and bulk SR [Ca 2ϩ ] as fixed boundary conditions. Conversely, modeling studies (4, 10, 40) focusing on cellular Ca 2ϩ transients have usually used representations of SR Ca 2ϩ release that do not account for the stochastic nature of the local events. Attempting to simulate Ca 2ϩ signaling at both spatial scales simultaneously is a daunting prospect because the stochastic behavior of thousands of local events must be considered to determine the effects on the bulk concentrations. As a result, only a few studies (16, 17, 49, 50) have attempted to capture both phenomena.

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supporting

confidence: 88%

Spontaneous Ca²⁺ sparks and Ca²⁺ homeostasis in a minimal model of permeabilized ventricular myocytes

Hartman

Sobie

Smith

2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…Unexpectedly, we observed that the behavior of SCaEs in R33Q myocytes is markedly different from that observed in myocytes derived from our RyR2 R4496C+/− CPVT mouse model 21 and from the data obtained in published models of recessive CPVT. 13,22 R33Q myocytes showed an abnormally short coupling of SCaEs to the previous paced activation and a remarkable fragmentation of the SCaEs. Cells isolated from the heart of RyR2 R4496C+/− mice seldom develop SCaEs between paced beats and present with well-organized Ca 2+ release events that propagate quickly to form a typical cell-wide wave.…”

Section: Discussionmentioning

confidence: 95%

Abnormal Propagation of Calcium Waves and Ultrastructural Remodeling in Recessive Catecholaminergic Polymorphic Ventricular Tachycardia

Liu

Denegri

Dun

et al. 2013

Circulation Research

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C atecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by stress-and emotion-induced life-threatening arrhythmias. Mutations in the cardiac ryanodine receptor-2 (RyR2) and cardiac calsequestrin-2 (CASQ2) genes have been associated with the autosomal-dominant and the autosomalrecessive forms of CPVT.1 Knock-in mouse models that carry gain-of-function RyR2 mutations exhibit phenotypes similar to the clinical manifestations observed in patients with CPVT, including the development of bidirectional/polymorphic VT on exposure to catecholamines.2-5 Investigations of knock-in models of dominant CPVT have demonstrated that abnormal Ca 2+ release from mutant RyR2 induces cell-wide Ca 2+ waves, delayed afterdepolarizations (DADs) and triggered activity, all of which are arrhythmogenic. 2,4,6 Recently, attention has turned to the study of the recessive form of CPVT that is caused by homozygous mutations in the CASQ2 gene. Most experimental studies on recessive CPVT have been performed using CASQ2 knockout mice, whereas only few knock-in mouse carriers of human CASQ2 mutations sparks with shortened coupling intervals, suggesting a reduced refractoriness of Ca 2+ release events; (3) have a reduction of the area of membrane contact, of the junctions between junctional sarcoplasmic reticulum and T tubules (couplons), and of junctional sarcoplasmic reticulum volume; (4) have a propensity to develop phase 2 to 4 afterdepolarizations that can elicit triggered beats; and (5) involve viral gene transfer with wild-type cardiac calsequestrin-2 that is able to normalize structural abnormalities and to restore cell-wide calcium wave propagation. Conclusions:Our data show that homozygous cardiac calsequestrin-2-R33Q myocytes develop spontaneous Ca 2+ release events with a broad range of intervals coupled to preceding beats, leading to the formation of early and delayed afterdepolarizations. They also display a major disruption of the Ca 2+ release unit architecture that leads to fragmentation of spontaneous Ca 2+ waves. We propose that these 2 substrates in R33Q myocytes synergize to provide a new arrhythmogenic mechanism for catecholaminergic polymorphic ventricular tachycardia. (Circ Res. 2013;113:142-152.)

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“…The mean puffs/spark duration was calculated using the matrix analytic method described in [39]. As K C decreases, the channels are more likely to be sensitized, the puff/spark duration increases, indicating that the luminal regulation of the channel might lead to longer puffs/sparks, which is consistant with experimental observations [38,40]. Compared to the Ca 2+ release site model composed of 10 two-state channels (filled circle), the average puff/spark duration of a release site composed of the same number of four-state channels can be up to four times (when K C = 1 ) longer.…”

Section: Reducing Ca 2+ Release Site Models That Are Composed Of Fourmentioning

confidence: 63%

“…An important motivation in using this four-state model is that luminal regulation of RyRs is observed in many experiments [37,38] but the detailed mechanism is yet not clear. In this paper, we are interested in how the "sensitization" of the activation of each individual Ca 2+ channel affects the cooperative gating of the Ca 2+ release site.…”

Section: Reducing Ca 2+ Release Site Models That Are Composed Of Fourmentioning

confidence: 99%

Reduction of calcium release site models via optimized state aggregation

Hao

2016

EPJ Nonlinear Biomed Phys

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Background: Markov chain models of calcium release sites in living cells exhibit stochastic dynamics reminiscent of the experimentally observed phenomenon of calcium puffs and sparks. Such models often take the form of stochastic automata networks in which the transition probabilities for each of a large number of intercellular channel models depend on the local calcium concentration and thus the state of nearby channels. The state-space size in such compositionally defined calcium release site models increases exponentially as the number of channels increases, which is referred to as "state-space explosion". Methods: In order to overcome the state-space explosion problem, we utilized the idea of "coarse graining" and implemented an automated procedure that reduces the state space by aggregating and lumping states of the full release site model. For a given state aggregation scheme, the transition rates between reduced states are chosen consistent with the conditional probability distribution among states within each group. A genetic algorithm-based approach is then applied to select the state aggregation schemes that lead to reduced models that approximate the observable behaviors of the full model. Results: The genetic algorithm-based approach is implemented in Matlab® and applied to two different release site models. The approach found reduced models that approximate the full model in the number of open channels, spark statistics, and the jump probability matrix as a function of time. Conclusions: A novel automated genetic algorithm-based searching technique is implemented to find reduced calcium release site models that approximate observable behaviors of the full Markov chain models that possess intractable state-spaces. As compared to the full model, the reduced models produce quantitatively similar results using significantly less computational resources.

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Intra‐sarcoplasmic reticulum Ca²⁺ oscillations are driven by dynamic regulation of ryanodine receptor function by luminal Ca²⁺ in cardiomyocytes

Cited by 46 publications

References 41 publications

Spontaneous Ca²⁺ sparks and Ca²⁺ homeostasis in a minimal model of permeabilized ventricular myocytes

Spontaneous Ca²⁺ sparks and Ca²⁺ homeostasis in a minimal model of permeabilized ventricular myocytes

Abnormal Propagation of Calcium Waves and Ultrastructural Remodeling in Recessive Catecholaminergic Polymorphic Ventricular Tachycardia

Reduction of calcium release site models via optimized state aggregation

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Intra‐sarcoplasmic reticulum Ca2+ oscillations are driven by dynamic regulation of ryanodine receptor function by luminal Ca2+ in cardiomyocytes

Cited by 46 publications

References 41 publications

Spontaneous Ca2+ sparks and Ca2+ homeostasis in a minimal model of permeabilized ventricular myocytes

Spontaneous Ca2+ sparks and Ca2+ homeostasis in a minimal model of permeabilized ventricular myocytes

Abnormal Propagation of Calcium Waves and Ultrastructural Remodeling in Recessive Catecholaminergic Polymorphic Ventricular Tachycardia

Reduction of calcium release site models via optimized state aggregation

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Intra‐sarcoplasmic reticulum Ca²⁺ oscillations are driven by dynamic regulation of ryanodine receptor function by luminal Ca²⁺ in cardiomyocytes

Spontaneous Ca²⁺ sparks and Ca²⁺ homeostasis in a minimal model of permeabilized ventricular myocytes

Spontaneous Ca²⁺ sparks and Ca²⁺ homeostasis in a minimal model of permeabilized ventricular myocytes