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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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Structure of the model. The model consists of 10,000 independent couplons, each with a dense square cluster of RyRs in a dyadic cleft, with an associated JSR release terminal. The JSR is refilled by intra-lumenal diffusion from calcium in the FSR (SR uptake compartment), which is assumed to be an infinite compartment at resting calcium CaSR0 because isolated sparks are being considered. Two models of the refilling connection were considered. In the simplest (A), the JSR refills through a single diffusional resistance, characterized by the refilling rate constant Dup. As discussed in the Results, it is difficult to reconcile the observed refilling rate with simple diffusion theory. We therefore constructed a second version of the model (B) in which the connection is made through a tube of local FSR, whose length and diameter are chosen to match the observed steady-state diffusion resistance (characterized by time constant τfill) and the observed volume fraction of FSR. For the standard parameters and a true half-sarcomere length of 1 µm, the effective SR tube length is 1.995 µm.
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fig1: Structure of the model. The model consists of 10,000 independent couplons, each with a dense square cluster of RyRs in a dyadic cleft, with an associated JSR release terminal. The JSR is refilled by intra-lumenal diffusion from calcium in the FSR (SR uptake compartment), which is assumed to be an infinite compartment at resting calcium CaSR0 because isolated sparks are being considered. Two models of the refilling connection were considered. In the simplest (A), the JSR refills through a single diffusional resistance, characterized by the refilling rate constant Dup. As discussed in the Results, it is difficult to reconcile the observed refilling rate with simple diffusion theory. We therefore constructed a second version of the model (B) in which the connection is made through a tube of local FSR, whose length and diameter are chosen to match the observed steady-state diffusion resistance (characterized by time constant τfill) and the observed volume fraction of FSR. For the standard parameters and a true half-sarcomere length of 1 µm, the effective SR tube length is 1.995 µm.

Mentions: Calcium sparks were simulated by an extension of a stochastic algorithm described previously (Stern et al., 1999). In brief, the algorithm generated a statistical ensemble of 10,000 realizations of a model couplon consisting in a square array of RyRs located on a 30-nm lattice in a dyadic cleft. Sparks were initiated by randomly opening one RyR in the couplon. Dyadic cleft [Ca2+] was calculated by a reaction–diffusion equation discretized on a two-dimensional 10-nm grid as described previously (Stern et al., 1999). In addition, the differential system now included a JSR compartment, with instantaneous buffering by Casq, and, optionally, a chain of free SR (FSR) compartments without buffering. The JSR compartment (Fig. 1) was coupled to an infinite pool of FSR calcium through either a single-diffusion resistance (Fig. 1 A) or a chain of 100 compartments simulating the local FSR of the sarcomere (Fig. 1 B). The joint gating of the RyRs in a couplon was simulated by a Monte Carlo algorithm that produces an exact realization of the variable-rate, continuous-time Markov process driven by the evolving cleft calcium distribution (Stern et al., 1997).


Life and death of a cardiac calcium spark.

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

Structure of the model. The model consists of 10,000 independent couplons, each with a dense square cluster of RyRs in a dyadic cleft, with an associated JSR release terminal. The JSR is refilled by intra-lumenal diffusion from calcium in the FSR (SR uptake compartment), which is assumed to be an infinite compartment at resting calcium CaSR0 because isolated sparks are being considered. Two models of the refilling connection were considered. In the simplest (A), the JSR refills through a single diffusional resistance, characterized by the refilling rate constant Dup. As discussed in the Results, it is difficult to reconcile the observed refilling rate with simple diffusion theory. We therefore constructed a second version of the model (B) in which the connection is made through a tube of local FSR, whose length and diameter are chosen to match the observed steady-state diffusion resistance (characterized by time constant τfill) and the observed volume fraction of FSR. For the standard parameters and a true half-sarcomere length of 1 µm, the effective SR tube length is 1.995 µm.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig1: Structure of the model. The model consists of 10,000 independent couplons, each with a dense square cluster of RyRs in a dyadic cleft, with an associated JSR release terminal. The JSR is refilled by intra-lumenal diffusion from calcium in the FSR (SR uptake compartment), which is assumed to be an infinite compartment at resting calcium CaSR0 because isolated sparks are being considered. Two models of the refilling connection were considered. In the simplest (A), the JSR refills through a single diffusional resistance, characterized by the refilling rate constant Dup. As discussed in the Results, it is difficult to reconcile the observed refilling rate with simple diffusion theory. We therefore constructed a second version of the model (B) in which the connection is made through a tube of local FSR, whose length and diameter are chosen to match the observed steady-state diffusion resistance (characterized by time constant τfill) and the observed volume fraction of FSR. For the standard parameters and a true half-sarcomere length of 1 µm, the effective SR tube length is 1.995 µm.
Mentions: Calcium sparks were simulated by an extension of a stochastic algorithm described previously (Stern et al., 1999). In brief, the algorithm generated a statistical ensemble of 10,000 realizations of a model couplon consisting in a square array of RyRs located on a 30-nm lattice in a dyadic cleft. Sparks were initiated by randomly opening one RyR in the couplon. Dyadic cleft [Ca2+] was calculated by a reaction–diffusion equation discretized on a two-dimensional 10-nm grid as described previously (Stern et al., 1999). In addition, the differential system now included a JSR compartment, with instantaneous buffering by Casq, and, optionally, a chain of free SR (FSR) compartments without buffering. The JSR compartment (Fig. 1) was coupled to an infinite pool of FSR calcium through either a single-diffusion resistance (Fig. 1 A) or a chain of 100 compartments simulating the local FSR of the sarcomere (Fig. 1 B). The joint gating of the RyRs in a couplon was simulated by a Monte Carlo algorithm that produces an exact realization of the variable-rate, continuous-time Markov process driven by the evolving cleft calcium distribution (Stern et al., 1997).

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