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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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Histograms of spark extinction time with and without the lumenal activation factor multiplying the RyR opening rate (Eq. 1.1). The lumenal activation factor provides about a 10-fold variation in opening rate over the range of JSR calcium concentrations during a spark, but its absence causes only a modest prolongation of RyR opening, and sparks still terminate based entirely on the direct effect of JSR depletion to reduce RyR flux and CICR loop gain.
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fig4: Histograms of spark extinction time with and without the lumenal activation factor multiplying the RyR opening rate (Eq. 1.1). The lumenal activation factor provides about a 10-fold variation in opening rate over the range of JSR calcium concentrations during a spark, but its absence causes only a modest prolongation of RyR opening, and sparks still terminate based entirely on the direct effect of JSR depletion to reduce RyR flux and CICR loop gain.

Mentions: Implicit in the histogram of Fig. 3 is that sparks do self-extinguish in a reasonable time. In other words, under the assumed conditions, JSR depletion provides a sufficient spark termination mechanism without requiring any RyR inactivation process. As shown in Fig. 4, this termination does not require the dependence of RyR gating on lumenal [Ca2+]. Spark extinction time was only modestly increased when lumenal activation was turned off. This shows that the interruption of positive feedback of CICR among RyRs within a couplon–by reduction in RyR flux as the JSR becomes locally depleted–is a sufficient mechanism to terminate sparks (as also shown by two models recently published: Gillespie and Fill, 2013, and Laver et al., 2013).


Life and death of a cardiac calcium spark.

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

Histograms of spark extinction time with and without the lumenal activation factor multiplying the RyR opening rate (Eq. 1.1). The lumenal activation factor provides about a 10-fold variation in opening rate over the range of JSR calcium concentrations during a spark, but its absence causes only a modest prolongation of RyR opening, and sparks still terminate based entirely on the direct effect of JSR depletion to reduce RyR flux and CICR loop gain.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig4: Histograms of spark extinction time with and without the lumenal activation factor multiplying the RyR opening rate (Eq. 1.1). The lumenal activation factor provides about a 10-fold variation in opening rate over the range of JSR calcium concentrations during a spark, but its absence causes only a modest prolongation of RyR opening, and sparks still terminate based entirely on the direct effect of JSR depletion to reduce RyR flux and CICR loop gain.
Mentions: Implicit in the histogram of Fig. 3 is that sparks do self-extinguish in a reasonable time. In other words, under the assumed conditions, JSR depletion provides a sufficient spark termination mechanism without requiring any RyR inactivation process. As shown in Fig. 4, this termination does not require the dependence of RyR gating on lumenal [Ca2+]. Spark extinction time was only modestly increased when lumenal activation was turned off. This shows that the interruption of positive feedback of CICR among RyRs within a couplon–by reduction in RyR flux as the JSR becomes locally depleted–is a sufficient mechanism to terminate sparks (as also shown by two models recently published: Gillespie and Fill, 2013, and Laver et al., 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.

Show MeSH
Related in: MedlinePlus