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Life and death of a cardiac calcium spark.

Stern MD, Ríos E, Maltsev VA - J. Gen. Physiol. (2013)

Bottom Line: We performed numerical simulations of an idealized stochastic model of spark production, assuming a RyR gating scheme with only two states (open and closed).Local depletion of calcium in the SR was inevitable during a spark, and this could terminate sparks by interrupting CICR, with or without assumed modulation of RyR gating by SR lumenal calcium.Using a highly simplified, deterministic model of the dynamics of a couplon, we show that spark metastability depends on the kinetic relationship of RyR gating and junctional SR refilling rates.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. SternMi@mail.nih.gov

ABSTRACT
Calcium sparks in cardiac myocytes are brief, localized calcium releases from the sarcoplasmic reticulum (SR) believed to be caused by locally regenerative calcium-induced calcium release (CICR) via couplons, clusters of ryanodine receptors (RyRs). How such regeneration is terminated is uncertain. We performed numerical simulations of an idealized stochastic model of spark production, assuming a RyR gating scheme with only two states (open and closed). Local depletion of calcium in the SR was inevitable during a spark, and this could terminate sparks by interrupting CICR, with or without assumed modulation of RyR gating by SR lumenal calcium. Spark termination by local SR depletion was not robust: under some conditions, sparks could be greatly and variably prolonged, terminating by stochastic attrition-a phenomenon we dub "spark metastability." Spark fluorescence rise time was not a good surrogate for the duration of calcium release. Using a highly simplified, deterministic model of the dynamics of a couplon, we show that spark metastability depends on the kinetic relationship of RyR gating and junctional SR refilling rates. The conditions for spark metastability resemble those produced by known mutations of RyR2 and CASQ2 that cause life-threatening triggered arrhythmias, and spark metastability may be mitigated by altering the kinetics of the RyR in a manner similar to the effects of drugs known to prevent those arrhythmias. The model was unable to explain the distributions of spark amplitudes and rise times seen in chemically skinned cat atrial myocytes, suggesting that such sparks may be more complex events involving heterogeneity of couplons or local propagation among sub-clusters of RyRs.

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Spark extinction time distributions as a function of assumed free calcium diffusion coefficient in the dyadic cleft. In these simulations, couplons consisted of 7 × 7 RyRs, with kom = 0.117 ms−1, Ca50 = 10 µM, JSR volume of 0.35% of cell volume divided among 20,000 couplons, and refilling time constant of 90 ms in the presence of 30 mM Casq. Only detected sparks that terminated within 300 ms are included in the histograms.
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fig14: Spark extinction time distributions as a function of assumed free calcium diffusion coefficient in the dyadic cleft. In these simulations, couplons consisted of 7 × 7 RyRs, with kom = 0.117 ms−1, Ca50 = 10 µM, JSR volume of 0.35% of cell volume divided among 20,000 couplons, and refilling time constant of 90 ms in the presence of 30 mM Casq. Only detected sparks that terminated within 300 ms are included in the histograms.

Mentions: Fig. 14 shows the distributions of spark extinction times assuming RyR kinetics derived from the results of Guo et al. (2012) as described above, and using values of DCa of 0.7, 0.35, 0.15, or 0.07 µ2/ms. It is apparent that the degree of spark metastability is markedly increased by restricted calcium diffusion in the cleft; for the value of DCa implied by Tadross et al. (2012), 75% of sparks fail to terminate within 1 s. This problem cannot be dealt with by rescaling the model: cleft geometry is constrained by ultrastructure, JSR contents are constrained by ultrastructure and biochemical measurements of CSQ, and RyR kinetics and conductance are constrained by lipid bilayer studies, so CICR loop gain is determined once DCa has been specified. This places a premium on understanding the extent to which diffusion and channel properties are modified by the in situ environment of the cleft.


Life and death of a cardiac calcium spark.

Stern MD, Ríos E, Maltsev VA - J. Gen. Physiol. (2013)

Spark extinction time distributions as a function of assumed free calcium diffusion coefficient in the dyadic cleft. In these simulations, couplons consisted of 7 × 7 RyRs, with kom = 0.117 ms−1, Ca50 = 10 µM, JSR volume of 0.35% of cell volume divided among 20,000 couplons, and refilling time constant of 90 ms in the presence of 30 mM Casq. Only detected sparks that terminated within 300 ms are included in the histograms.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3753601&req=5

fig14: Spark extinction time distributions as a function of assumed free calcium diffusion coefficient in the dyadic cleft. In these simulations, couplons consisted of 7 × 7 RyRs, with kom = 0.117 ms−1, Ca50 = 10 µM, JSR volume of 0.35% of cell volume divided among 20,000 couplons, and refilling time constant of 90 ms in the presence of 30 mM Casq. Only detected sparks that terminated within 300 ms are included in the histograms.
Mentions: Fig. 14 shows the distributions of spark extinction times assuming RyR kinetics derived from the results of Guo et al. (2012) as described above, and using values of DCa of 0.7, 0.35, 0.15, or 0.07 µ2/ms. It is apparent that the degree of spark metastability is markedly increased by restricted calcium diffusion in the cleft; for the value of DCa implied by Tadross et al. (2012), 75% of sparks fail to terminate within 1 s. This problem cannot be dealt with by rescaling the model: cleft geometry is constrained by ultrastructure, JSR contents are constrained by ultrastructure and biochemical measurements of CSQ, and RyR kinetics and conductance are constrained by lipid bilayer studies, so CICR loop gain is determined once DCa has been specified. This places a premium on understanding the extent to which diffusion and channel properties are modified by the in situ environment of the cleft.

Bottom Line: We performed numerical simulations of an idealized stochastic model of spark production, assuming a RyR gating scheme with only two states (open and closed).Local depletion of calcium in the SR was inevitable during a spark, and this could terminate sparks by interrupting CICR, with or without assumed modulation of RyR gating by SR lumenal calcium.Using a highly simplified, deterministic model of the dynamics of a couplon, we show that spark metastability depends on the kinetic relationship of RyR gating and junctional SR refilling rates.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. SternMi@mail.nih.gov

ABSTRACT
Calcium sparks in cardiac myocytes are brief, localized calcium releases from the sarcoplasmic reticulum (SR) believed to be caused by locally regenerative calcium-induced calcium release (CICR) via couplons, clusters of ryanodine receptors (RyRs). How such regeneration is terminated is uncertain. We performed numerical simulations of an idealized stochastic model of spark production, assuming a RyR gating scheme with only two states (open and closed). Local depletion of calcium in the SR was inevitable during a spark, and this could terminate sparks by interrupting CICR, with or without assumed modulation of RyR gating by SR lumenal calcium. Spark termination by local SR depletion was not robust: under some conditions, sparks could be greatly and variably prolonged, terminating by stochastic attrition-a phenomenon we dub "spark metastability." Spark fluorescence rise time was not a good surrogate for the duration of calcium release. Using a highly simplified, deterministic model of the dynamics of a couplon, we show that spark metastability depends on the kinetic relationship of RyR gating and junctional SR refilling rates. The conditions for spark metastability resemble those produced by known mutations of RyR2 and CASQ2 that cause life-threatening triggered arrhythmias, and spark metastability may be mitigated by altering the kinetics of the RyR in a manner similar to the effects of drugs known to prevent those arrhythmias. The model was unable to explain the distributions of spark amplitudes and rise times seen in chemically skinned cat atrial myocytes, suggesting that such sparks may be more complex events involving heterogeneity of couplons or local propagation among sub-clusters of RyRs.

Show MeSH
Related in: MedlinePlus