Ryanodine receptor adaptation and Ca2+(-)induced Ca2+ release-dependent Ca2+ oscillations

Keizer, Joel; Levine, Lawrence W.

doi:10.1016/s0006-3495(96)79543-7

Cited by 162 publications

(173 citation statements)

References 31 publications

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“…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. While in prior work [21], similar comparisons to a Ca 2+ release site composed of Keizer-Levine model [41] and its corresponding reduced model gave good agreement, in this new study the reduced model tends to slightly underestimate the puff/spark durations.…”

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

confidence: 60%

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

confidence: 60%

Reduction of calcium release site models via optimized state aggregation

Hao

2016

EPJ Nonlinear Biomed Phys

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“…However, the regulation of RyRs is still an issue in debate, which is summarized in a recent review article by Sobie and Lederer (60). Nevertheless, many RyR models (11,28,31,49,59,61,70,72) have been developed and used to study Ca cycling dynamics in cardiac myocytes. We expect that a specific RyR model may give specific predictions of the effects of a physiological parameter on Ca alternans, but we also believe that these specific effects can be mechanistically unified using the 3R theory.…”

Section: Limitationsmentioning

confidence: 99%

Calcium alternans in a couplon network model of ventricular myocytes: role of sarcoplasmic reticulum load

Nivala

2012

American Journal of Physiology-Heart and Circulatory Physiology

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Nivala M, Qu Z. Calcium alternans in a couplon network model of ventricular myocytes: role of sarcoplasmic reticulum load. Am J Physiol Heart Circ Physiol 303: H341-H352, 2012. First published June 1, 2012; doi:10.1152/ajpheart.00302.2012.-Intracellular calcium (Ca) alternans in cardiac myocytes have been shown in many experimental studies, and the mechanisms remain incompletely understood. We recently developed a "3R theory" that links Ca sparks to whole cell Ca alternans through three critical properties: randomness of Ca sparks; recruitment of a Ca spark by neighboring Ca sparks; and refractoriness of Ca release units. In this study, we used computer simulation of a physiologically detailed mathematical model of a ventricular myocyte couplon network to study how sarcoplasmic reticulum (SR) Ca load and other physiological parameters, such as ryanodine receptor sensitivity, SR uptake rate, Na-Ca exchange strength, and Ca buffer levels affect Ca alternans in the context of 3R theory. We developed a method to calculate the parameters used in the 3R theory (i.e., the primary spark rate and the recruitment rate) from the physiologically detailed Ca cycling model and paced the model periodically to elicit Ca alternans. We show that alternans only occurs for an intermediate range of the SR Ca load, and the underlying mechanism can be explained via its effects on the 3Rs. Furthermore, we show that altering the physiological parameters not only directly changes the 3Rs but also alters the SR Ca load, having an indirect effect on the 3Rs as well. Therefore, our present study links the SR Ca load and other physiological parameters to whole cell Ca alternans through the framework of the 3R theory, providing a general mechanistic understanding of Ca alternans in ventricular myocytes. calcium cycling; calcium spark; modeling T-WAVE ALTERNANS HAVE BEEN closely associated with cardiac arrhythmias and sudden cardiac death (3,50,51,66,69). Intracellular calcium (Ca) alternans, as a potential cause of T-wave alternans (15,46), have been shown in many experimental studies (2, 5, 7, 16 -19, 25, 35, 41, 68, 71). However, the underlying mechanism of Ca alternans remains incompletely understood. Adler et al. (1) proposed a theoretical mechanism linking a nonlinear sarcoplasmic reticulum (SR) Ca release function to mechanical alternans. Evidence from experimental studies (17)(18)(19)71) shows that Ca alternans could be explained by a steep nonlinear dependence of SR Ca release upon the diastolic SR Ca load (Ca DSRL ) immediately preceding the release (a steep fractional release-load relationship). This mechanism requires that Ca DSRL alternate concomitantly with SR Ca release, but the refractoriness of SR Ca release is not explicitly required. Subsequent mathematical analyses and simulation studies either potentiated this theory (30,45,57,64,69,71) (41), and the importance of refractoriness in Ca alternans has been demonstrated in later studies (32,58). Therefore, the above experimental studies raise the issue of the roles of SR Ca an...

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“…25 In isolated bilayers, adaptation occurs within milliseconds, whereas inactivation occurs within a few seconds. 23 A state diagram of the RyR2 model is shown in Figure 1. This model has 2 open states (O1 and O2) and 2 closed states (C1 and C2).…”

Section: The Ryr2 Modelmentioning

confidence: 99%

Mechanisms of Abnormal Calcium Homeostasis in Mutations Responsible for Catecholaminergic Polymorphic Ventricular Tachycardia

Iyer

Hajjar

Armoundas

2007

Circulation Research

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Abstract-Catecholaminergic polymorphic ventricular tachycardia is a heritable arrhythmia unmasked by exertion or stress and is characterized by triggered activity and sudden cardiac death. In this study, we simulated mutations in 2 genes linked to catecholaminergic polymorphic ventricular tachycardia, the first located in calsequestrin (CSQN2) and the second in the ryanodine receptor (RyR2). The aim of the study was to investigate the mechanistic basis for spontaneous Ca 2ϩ release events that lead to delayed afterdepolarizations in affected patients. Sarcoplasmic reticulum (SR) luminal Ca 2ϩ sensing was incorporated into a model of the human ventricular myocyte, and CSQN2 mutations were modeled by simulating disrupted RyR2 luminal Ca 2ϩ sensing. In voltage-clamp mode, the mutant CSQN2 model recapitulated the smaller calcium transients, smaller time to peak calcium transient, and accelerated recovery from inactivation seen in experiments. In current clamp mode, in the presence of ␤ stimulation, we observed delayed afterdepolarizations, suggesting that accelerated recovery of RyR2 induced by impaired luminal Ca 2ϩ sensing underlies the triggered activity observed in mutant CSQN2-expressing myocytes. In current-clamp mode, in a model of mutant RyR2 that is characterized by reduced FKBP12.6 binding to the RyR2 on ␤ stimulation, the impaired coupled gating characteristic of these mutations was modeled by reducing cooperativity of RyR2 activation. In current-clamp mode, the mutant RyR2 model exhibited increased diastolic RyR2 open probability that resulted in formation of delayed afterdepolarizations. In conclusion, these minimal order models of mutant CSQN2 and RyR2 provide plausible mechanisms by which defects in RyR2 gating may lead to the cellular triggers for arrhythmia, with implications for the development of targeted therapy. (Circ Res. 2007;100:e22-e31.) Key Words: catecholaminergic polymorphic ventricular tachycardia Ⅲ delayed afterdepolarization Ⅲ ryanodine receptor Ⅲ calsequestrin Ⅲ calcium handling Ⅲ simulation C atecholaminergic polymorphic ventricular tachycardia (CPVT) is a heritable arrhythmia unmasked by exertion or stress. Mutations in the cardiac ryanodine receptor 2 (RyR2, gene RYR2) 1-3 and the calcium buffer calsequestrin 2 (CSQN2, gene CASQ2) 4,5 have been reported in families affected by the disorder. More than 40 mutations have been identified thus far, with many additional mutants constantly being added to the spectrum of disease-linked gene products. 6 -8 The rate of discovery of newly identified CPVT mutations has outpaced the experimental characterization of the function of the mutant gene products. Indeed, much controversy still exists regarding the cellular mechanisms by which these mutations cause arrhythmias. Hypotheses have been advanced on the basis of recent experimental characterizations in transgenic animal models, 9 in ventricular myocytes, 10,11 and in lipid bilayers. 12 Evidence suggests that the RyR2 exists in a supramolecular release complex along with CSQN2 at junctio...

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Ryanodine receptor adaptation and Ca2+(-)induced Ca2+ release-dependent Ca2+ oscillations

Cited by 162 publications

References 31 publications

Reduction of calcium release site models via optimized state aggregation

Reduction of calcium release site models via optimized state aggregation

Calcium alternans in a couplon network model of ventricular myocytes: role of sarcoplasmic reticulum load

Mechanisms of Abnormal Calcium Homeostasis in Mutations Responsible for Catecholaminergic Polymorphic Ventricular Tachycardia

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