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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.

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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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The nadir of JSR calcium during a simulated spark is low unless RyR closing rate is strongly regulated by lumenal calcium. (A) Distributions of the nadir of [Ca2+]JSR of simulated stochastic sparks with (green) or without (red) the lumenal activation factor in Eq. 1.1. Lumenal deactivation when the JSR is depleted contributes to termination of the spark at somewhat higher [Ca2+]JSR, but the nadir is quite low in both cases, which is not compatible with the idea that the spark is shut off when lumenal calcium falls to a “threshold” of ∼50%. (B) Attempt to reproduce the 50% nadir by lowering the RyR mean open time so that sparks will extinguish promptly once CICR is no longer regenerative, and reducing the opening rate constant. This required RyR sensitivity so low that only 7% of attempted sparks were detectable, and they were very stochastic and either abortive or low amplitude. (C) A well-defined 40% nadir was produced by making the RyR mean open time strongly and nonlinearly dependent on [Ca2+]JSR, thereby forcing RyRs to close below the threshold.
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fig12: The nadir of JSR calcium during a simulated spark is low unless RyR closing rate is strongly regulated by lumenal calcium. (A) Distributions of the nadir of [Ca2+]JSR of simulated stochastic sparks with (green) or without (red) the lumenal activation factor in Eq. 1.1. Lumenal deactivation when the JSR is depleted contributes to termination of the spark at somewhat higher [Ca2+]JSR, but the nadir is quite low in both cases, which is not compatible with the idea that the spark is shut off when lumenal calcium falls to a “threshold” of ∼50%. (B) Attempt to reproduce the 50% nadir by lowering the RyR mean open time so that sparks will extinguish promptly once CICR is no longer regenerative, and reducing the opening rate constant. This required RyR sensitivity so low that only 7% of attempted sparks were detectable, and they were very stochastic and either abortive or low amplitude. (C) A well-defined 40% nadir was produced by making the RyR mean open time strongly and nonlinearly dependent on [Ca2+]JSR, thereby forcing RyRs to close below the threshold.

Mentions: Fig. 12 A shows the distribution of the nadir of JSR free calcium during a spark, with or without lumenal modulation of RyR gating. The fraction of calcium remaining in the JSR after a spark is quite low, as has been found in other models (Sobie et al., 2002; Ramay et al., 2011; Laver et al., 2013). This is at variance with blink observations showing only ∼50% depletion, as well as with the common idea that JSR calcium falls to a “threshold” of ∼50% at which point lumenal deactivation terminates the spark.


Life and death of a cardiac calcium spark.

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

The nadir of JSR calcium during a simulated spark is low unless RyR closing rate is strongly regulated by lumenal calcium. (A) Distributions of the nadir of [Ca2+]JSR of simulated stochastic sparks with (green) or without (red) the lumenal activation factor in Eq. 1.1. Lumenal deactivation when the JSR is depleted contributes to termination of the spark at somewhat higher [Ca2+]JSR, but the nadir is quite low in both cases, which is not compatible with the idea that the spark is shut off when lumenal calcium falls to a “threshold” of ∼50%. (B) Attempt to reproduce the 50% nadir by lowering the RyR mean open time so that sparks will extinguish promptly once CICR is no longer regenerative, and reducing the opening rate constant. This required RyR sensitivity so low that only 7% of attempted sparks were detectable, and they were very stochastic and either abortive or low amplitude. (C) A well-defined 40% nadir was produced by making the RyR mean open time strongly and nonlinearly dependent on [Ca2+]JSR, thereby forcing RyRs to close below the threshold.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig12: The nadir of JSR calcium during a simulated spark is low unless RyR closing rate is strongly regulated by lumenal calcium. (A) Distributions of the nadir of [Ca2+]JSR of simulated stochastic sparks with (green) or without (red) the lumenal activation factor in Eq. 1.1. Lumenal deactivation when the JSR is depleted contributes to termination of the spark at somewhat higher [Ca2+]JSR, but the nadir is quite low in both cases, which is not compatible with the idea that the spark is shut off when lumenal calcium falls to a “threshold” of ∼50%. (B) Attempt to reproduce the 50% nadir by lowering the RyR mean open time so that sparks will extinguish promptly once CICR is no longer regenerative, and reducing the opening rate constant. This required RyR sensitivity so low that only 7% of attempted sparks were detectable, and they were very stochastic and either abortive or low amplitude. (C) A well-defined 40% nadir was produced by making the RyR mean open time strongly and nonlinearly dependent on [Ca2+]JSR, thereby forcing RyRs to close below the threshold.
Mentions: Fig. 12 A shows the distribution of the nadir of JSR free calcium during a spark, with or without lumenal modulation of RyR gating. The fraction of calcium remaining in the JSR after a spark is quite low, as has been found in other models (Sobie et al., 2002; Ramay et al., 2011; Laver et al., 2013). This is at variance with blink observations showing only ∼50% depletion, as well as with the common idea that JSR calcium falls to a “threshold” of ∼50% at which point lumenal deactivation terminates the spark.

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