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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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An overlay of ∼50 sparks in the metastable regimen defined by the gating parameters from Guo et al. (2012) and the JSR refilling rate inferred from observed spark restitution. The metastability is only revealed by the presence of low amplitude embers after the peak of the spark.
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fig9: An overlay of ∼50 sparks in the metastable regimen defined by the gating parameters from Guo et al. (2012) and the JSR refilling rate inferred from observed spark restitution. The metastability is only revealed by the presence of low amplitude embers after the peak of the spark.

Mentions: As demonstrated by Picht et al. (2011) and confirmed by our simple spherically symmetric spark/blink computations (see above and supplemental text), the observed rates of blink recovery (∼200 ms in rabbit ventricle) and spark restitution (∼90 ms in rat using repeating sparks generated by micro-dose ryanodine; Sobie et al., 2005; Ramay et al., 2011) are not easily accounted for by simple models of calcium diffusion in the FSR lumen. Possible explanations are the presence of tortuosities or constrictions in the connection of the JSR to the FSR, or an error in the estimation of the intra-lumenal calcium diffusion rate. Picht et al. (2011), however, interpreted this discrepancy as evidence that there is a continuing tail of calcium release during the recovery from a blink, and that the time constant of recovery is limited by the decay of this release rather than by the rate of refilling from the FSR. Our analysis of spark metastability above makes this explanation problematic. If [Ca2+]SR recovers while some RyRs are still open, CICR will not extinguish: the spark would be metastable. On the assumption that metastable sparks are not a normal condition, we take this as evidence against Picht’s interpretation and favor the assumption that greater limitations on intra-SR diffusion are actually present. However, in the interest of open-mindedness, we must at least consider the hypothesis that “normal” spark/blink pairs are, in fact, metastable. For sparks that are terminated by a JSR depletion signal, the time-to-peak of spark fluorescence depends almost entirely on JSR volume, the number of RyRs recruited, and the resistance to efflux from the cleft. A metastable spark would only be recognized by a trailing “ember” (González et al., 2000) because of continuing release through open RyRs, fed by calcium returning from the FSR. Fig. 9 shows an overlay of 50 metastable sparks (F/F0 at the spark center). For these simulations, refilling rate was low but metastability was produced by raising the calcium sensitivity of the RyR. The resulting embers, although clearly visible in the noise-free simulation, might be difficult to detect under the conditions of confocal recording. Note also that the embers tend to be oscillatory. So called “sub-sparks” have in fact been noted after major sparks (Santiago et al., 2013) but have usually been attributed to recruitment of sub-clusters of RyRs. In our simulations, couplons are single crystalline arrays of RyRs, without satellite groupings, so oscillatory embers are a purely dynamical phenomenon (see Videos 1 and 2).


Life and death of a cardiac calcium spark.

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

An overlay of ∼50 sparks in the metastable regimen defined by the gating parameters from Guo et al. (2012) and the JSR refilling rate inferred from observed spark restitution. The metastability is only revealed by the presence of low amplitude embers after the peak of the spark.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig9: An overlay of ∼50 sparks in the metastable regimen defined by the gating parameters from Guo et al. (2012) and the JSR refilling rate inferred from observed spark restitution. The metastability is only revealed by the presence of low amplitude embers after the peak of the spark.
Mentions: As demonstrated by Picht et al. (2011) and confirmed by our simple spherically symmetric spark/blink computations (see above and supplemental text), the observed rates of blink recovery (∼200 ms in rabbit ventricle) and spark restitution (∼90 ms in rat using repeating sparks generated by micro-dose ryanodine; Sobie et al., 2005; Ramay et al., 2011) are not easily accounted for by simple models of calcium diffusion in the FSR lumen. Possible explanations are the presence of tortuosities or constrictions in the connection of the JSR to the FSR, or an error in the estimation of the intra-lumenal calcium diffusion rate. Picht et al. (2011), however, interpreted this discrepancy as evidence that there is a continuing tail of calcium release during the recovery from a blink, and that the time constant of recovery is limited by the decay of this release rather than by the rate of refilling from the FSR. Our analysis of spark metastability above makes this explanation problematic. If [Ca2+]SR recovers while some RyRs are still open, CICR will not extinguish: the spark would be metastable. On the assumption that metastable sparks are not a normal condition, we take this as evidence against Picht’s interpretation and favor the assumption that greater limitations on intra-SR diffusion are actually present. However, in the interest of open-mindedness, we must at least consider the hypothesis that “normal” spark/blink pairs are, in fact, metastable. For sparks that are terminated by a JSR depletion signal, the time-to-peak of spark fluorescence depends almost entirely on JSR volume, the number of RyRs recruited, and the resistance to efflux from the cleft. A metastable spark would only be recognized by a trailing “ember” (González et al., 2000) because of continuing release through open RyRs, fed by calcium returning from the FSR. Fig. 9 shows an overlay of 50 metastable sparks (F/F0 at the spark center). For these simulations, refilling rate was low but metastability was produced by raising the calcium sensitivity of the RyR. The resulting embers, although clearly visible in the noise-free simulation, might be difficult to detect under the conditions of confocal recording. Note also that the embers tend to be oscillatory. So called “sub-sparks” have in fact been noted after major sparks (Santiago et al., 2013) but have usually been attributed to recruitment of sub-clusters of RyRs. In our simulations, couplons are single crystalline arrays of RyRs, without satellite groupings, so oscillatory embers are a purely dynamical phenomenon (see Videos 1 and 2).

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