Effects of rogue ryanodine receptors on Ca 2+ sparks in cardiac myocytes

Figures

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  Figure 1.. Geometrical model. (a) Schematic representation of the 2D geometrical model of a cardiac myocyte. The yellow dots denote JSRs with regularly spaced intervals: lx = 2 µm and ly = 0.8 µm. (b) Schematic representation of a JSR, which includes randomly distributed clustered and rogue RyRs. (c) The distribution of clustered and rogue RyRs in a JSR for simulation (l = 0.1 µm). Two CRUs of clustered RyRs (blue dots) are surrounded by eight rogue RyRs (red dots) on the JSR as shown in (b). The number and location of clustered and rogue RyRs are random in simulations.

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  Figure 2.. Properties of Ca2+ quarks and Ca2+ sparks. (a) A computational line-scan Ca2+ quark through a rogue RyR (5 µm × 50 ms). (b) The corresponding time courses of a QCR–QCD pair. (c) A representative line-scan image (50 µm × 1 s) of Ca2+ release events measured in a cardiac myocyte. Arrows point to Ca2+ sparks activated by QCRs. (d) Experimental results for line-scan images of sparks activated by QCRs. (e) Computational results in agreement with (d).

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  Figure 3.. Interplay of rogue and clustered RyRs in a JSR. Snapshots of Ca2+ release events in a region of 5 µm × 5 µm are taken at 10, 20 and 40 ms from left to right when three rogue RyRs are fired at the same time. There are three distinct modes. Schematic interplay of Ca2+ release events is plotted below the snapshots. Clustered and rogue RyRs are distinguished by blue and red colours similar to figure 1c. Cytoplasmic Ca2+ is displayed by pink colour. Arrows denote that Ca2+ diffuses and activates neighbour clustered and rogue RyRs in the cytoplasm. SR, sarcoplasmic reticulum; TT, T-tubule. (a) No activated Ca2+ spark. Neighbour rogue RyRs are activated by Ca2+ quarks. (b) A Ca2+ spark with one quantal unit. One CRU of clustered RyRs is initiated by Ca2+ quarks. Then Ca2+ spark from the CRU of clustered RyRs contributes to activation of neighbour rogue RyRs. (c) A Ca2+ spark with two quantal units. Two CRUs of clustered RyRs are triggered and then activate neighbour rogue RyRs.

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  Figure 4.. The probability of activated quantal units in a JSR calculated by Monte Carlo simulations (n = 20).

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  Figure 5.. The firing frequency of Ca2+ sparks (red line) and quarks (blue line) determined by Monte Carlo simulations (n = 10) when [Ca2+]lumen varies from 0.2 mM to 1.0 mM.

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  Figure 6.. Effects of rogue RyRs on Ca2+ sparks as [Ca2+]lumen varies. (a) Computational line-scan Ca2+ release events (20 µm × 2 s) with effects of rogue RyRs when [Ca2+]lumen = 1.0 mM, 0.6 mM and 0.2 mM. Ca2+ sparks are marked by white ovals. (b) Computational line-scan Ca2+ release events without effects of rogue RyRs under the same conditions as (a). (c) Sensitivity analysis on the firing frequency of Ca2+ sparks as a function of the number of rogue RyRs in a JSR at various [Ca2+]lumen determined by Monte Carlo simulations (n = 10).

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  Figure 7.. Schematic interplay of clustered and rogue RyRs in neighbour JSRs. Clustered RyRs are triggered by Ca2+ sparks in a neighbour JSR with the help of rogue RyRs.