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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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Attempt to “pharmacologically treat” spark metastability. The black curve shows a histogram (log ordinate) of spark extinction times, assuming RyR gating rates estimated from the lipid bilayer data of Guo et al. (2012) and the JSR refilling rate estimated from spark restitution in rat (Sobie et al., 2005). As shown by the tail extending to long durations, these parameters give unstable sparks. The green curve shows the effect of doubling both the opening and closing rate constants of the RyR, thereby leaving the “calcium sensitivity” defined by po unchanged. This substantially shortens the unstable tail, because it accelerates RyR gating relative to the rate of refilling of the JSR. The red curve shows the additional effect of doubling the concentration of Casq, slowing down JSR depletion and refilling by increasing buffering. The peak of the distribution moves to the right, as expected, but the tail is actually shortened because JSR refilling is slower relative to RyR gating, reducing spark metastability.
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fig8: Attempt to “pharmacologically treat” spark metastability. The black curve shows a histogram (log ordinate) of spark extinction times, assuming RyR gating rates estimated from the lipid bilayer data of Guo et al. (2012) and the JSR refilling rate estimated from spark restitution in rat (Sobie et al., 2005). As shown by the tail extending to long durations, these parameters give unstable sparks. The green curve shows the effect of doubling both the opening and closing rate constants of the RyR, thereby leaving the “calcium sensitivity” defined by po unchanged. This substantially shortens the unstable tail, because it accelerates RyR gating relative to the rate of refilling of the JSR. The red curve shows the additional effect of doubling the concentration of Casq, slowing down JSR depletion and refilling by increasing buffering. The peak of the distribution moves to the right, as expected, but the tail is actually shortened because JSR refilling is slower relative to RyR gating, reducing spark metastability.

Mentions: Treatments that redress the kinetic balance should be helpful for such arrhythmias. Fig. 8 shows spark extinction time histograms (log ordinate scale) for a model with RyR gating rates taken from a two-state approximation to the lipid bilayer data of Guo et al. (2012) (see supplemental text for a discussion of the issues in making this estimate) and assuming Dup = 0.15. As seen from the black curve, these parameters (taken from observations in different kinds of experiments) actually give sparks that are somewhat metastable. The green curve shows the effect of simultaneously doubling the RyR opening and closing rate constants, keeping the po as a function of [Ca2+]cleft unchanged. This kinetic change substantially reduces the tail of metastable sparks. The red curve shows the additional effect of doubling the concentration of Casq, thereby slowing JSR depletion and refilling. Increasing Casq delays the peak of the histogram as expected, but the tail actually moves leftward as the refilling rate decreases compared with the RyR closure rate, reducing spark metastability. This offers a possible explanation for the observation that drugs, such as carvedilol and flecainide, that increase the RyR closure rate (decrease mean open time) have been effective in preventing calcium waves and catecholaminergic polymorphic ventricular tachycardia in animal models (Watanabe et al., 2009; Hilliard et al., 2010; Zhou et al., 2011).


Life and death of a cardiac calcium spark.

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

Attempt to “pharmacologically treat” spark metastability. The black curve shows a histogram (log ordinate) of spark extinction times, assuming RyR gating rates estimated from the lipid bilayer data of Guo et al. (2012) and the JSR refilling rate estimated from spark restitution in rat (Sobie et al., 2005). As shown by the tail extending to long durations, these parameters give unstable sparks. The green curve shows the effect of doubling both the opening and closing rate constants of the RyR, thereby leaving the “calcium sensitivity” defined by po unchanged. This substantially shortens the unstable tail, because it accelerates RyR gating relative to the rate of refilling of the JSR. The red curve shows the additional effect of doubling the concentration of Casq, slowing down JSR depletion and refilling by increasing buffering. The peak of the distribution moves to the right, as expected, but the tail is actually shortened because JSR refilling is slower relative to RyR gating, reducing spark metastability.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig8: Attempt to “pharmacologically treat” spark metastability. The black curve shows a histogram (log ordinate) of spark extinction times, assuming RyR gating rates estimated from the lipid bilayer data of Guo et al. (2012) and the JSR refilling rate estimated from spark restitution in rat (Sobie et al., 2005). As shown by the tail extending to long durations, these parameters give unstable sparks. The green curve shows the effect of doubling both the opening and closing rate constants of the RyR, thereby leaving the “calcium sensitivity” defined by po unchanged. This substantially shortens the unstable tail, because it accelerates RyR gating relative to the rate of refilling of the JSR. The red curve shows the additional effect of doubling the concentration of Casq, slowing down JSR depletion and refilling by increasing buffering. The peak of the distribution moves to the right, as expected, but the tail is actually shortened because JSR refilling is slower relative to RyR gating, reducing spark metastability.
Mentions: Treatments that redress the kinetic balance should be helpful for such arrhythmias. Fig. 8 shows spark extinction time histograms (log ordinate scale) for a model with RyR gating rates taken from a two-state approximation to the lipid bilayer data of Guo et al. (2012) (see supplemental text for a discussion of the issues in making this estimate) and assuming Dup = 0.15. As seen from the black curve, these parameters (taken from observations in different kinds of experiments) actually give sparks that are somewhat metastable. The green curve shows the effect of simultaneously doubling the RyR opening and closing rate constants, keeping the po as a function of [Ca2+]cleft unchanged. This kinetic change substantially reduces the tail of metastable sparks. The red curve shows the additional effect of doubling the concentration of Casq, thereby slowing JSR depletion and refilling. Increasing Casq delays the peak of the histogram as expected, but the tail actually moves leftward as the refilling rate decreases compared with the RyR closure rate, reducing spark metastability. This offers a possible explanation for the observation that drugs, such as carvedilol and flecainide, that increase the RyR closure rate (decrease mean open time) have been effective in preventing calcium waves and catecholaminergic polymorphic ventricular tachycardia in animal models (Watanabe et al., 2009; Hilliard et al., 2010; Zhou et al., 2011).

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