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Modulation of elementary calcium release mediates a transition from puffs to waves in an IP3R cluster model.

Rückl M, Parker I, Marchant JS, Nagaiah C, Johenning FW, Rüdiger S - PLoS Comput. Biol. (2015)

Bottom Line: For increasing IP3 concentration, the release events become modulated at a timescale of minutes, with repetitive wave-like releases interspersed with several puffs.This modulation is consistent with experimental observations we present, including refractoriness and increase of puff frequency during the inter-wave interval.Our results suggest that waves are established by a random but time-modulated appearance of sustained release events, which have a high potential to trigger and synchronize activity throughout the cell.

View Article: PubMed Central - PubMed

Affiliation: Institut für Physik, Humboldt-Universität zu Berlin, Berlin, Germany.

ABSTRACT
The oscillating concentration of intracellular calcium is one of the most important examples for collective dynamics in cell biology. Localized releases of calcium through clusters of inositol 1,4,5-trisphosphate receptor channels constitute elementary signals called calcium puffs. Coupling by diffusing calcium leads to global releases and waves, but the exact mechanism of inter-cluster coupling and triggering of waves is unknown. To elucidate the relation of puffs and waves, we here model a cluster of IP3R channels using a gating scheme with variable non-equilibrium IP3 binding. Hybrid stochastic and deterministic simulations show that puffs are not stereotyped events of constant duration but are sensitive to stimulation strength and residual calcium. For increasing IP3 concentration, the release events become modulated at a timescale of minutes, with repetitive wave-like releases interspersed with several puffs. This modulation is consistent with experimental observations we present, including refractoriness and increase of puff frequency during the inter-wave interval. Our results suggest that waves are established by a random but time-modulated appearance of sustained release events, which have a high potential to trigger and synchronize activity throughout the cell.

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Distribution of the number of activatable channels at the beginning of the events for [IP3] = 10 nM (red bars), 35 nM (green bars) and 75 nM (blue bars).Dashed lines mark the mean value. Inset: The average number of activatable channels at the beginning of an event depends on [IP3]. Vertical bars are standard deviations.
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pcbi-1003965-g004: Distribution of the number of activatable channels at the beginning of the events for [IP3] = 10 nM (red bars), 35 nM (green bars) and 75 nM (blue bars).Dashed lines mark the mean value. Inset: The average number of activatable channels at the beginning of an event depends on [IP3]. Vertical bars are standard deviations.

Mentions: We will now discuss how the impact of varying IP3 concentration on event lifetime is mediated by the dynamics of IP3 binding and unbinding, i.e. the dynamics of the number of activatable channels. Events with a higher number of participating channels will generally last longer (see below). A simple approach to elucidate this relation is to count the number of activatable channels at the beginning of each event. The distribution of this number of activatable channels is shown for three different IP3 concentrations in Fig. 4. Here we can find similar features as before: for increasing [IP3] the histogram gets skewed to the right leading to a much increased shoulder. Both the average and the standard deviation of the distribution increase with [IP3] (inset). However, the increase of the average number of activatable channels is relatively small, rising from four channels at [IP3] = 10 nM to about five channels at 80 nM. On the other hand, the variability doubles for the same range of [IP3]. Thus, it is plausible, that the increased variability determines the appearance of extended events.


Modulation of elementary calcium release mediates a transition from puffs to waves in an IP3R cluster model.

Rückl M, Parker I, Marchant JS, Nagaiah C, Johenning FW, Rüdiger S - PLoS Comput. Biol. (2015)

Distribution of the number of activatable channels at the beginning of the events for [IP3] = 10 nM (red bars), 35 nM (green bars) and 75 nM (blue bars).Dashed lines mark the mean value. Inset: The average number of activatable channels at the beginning of an event depends on [IP3]. Vertical bars are standard deviations.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4288706&req=5

pcbi-1003965-g004: Distribution of the number of activatable channels at the beginning of the events for [IP3] = 10 nM (red bars), 35 nM (green bars) and 75 nM (blue bars).Dashed lines mark the mean value. Inset: The average number of activatable channels at the beginning of an event depends on [IP3]. Vertical bars are standard deviations.
Mentions: We will now discuss how the impact of varying IP3 concentration on event lifetime is mediated by the dynamics of IP3 binding and unbinding, i.e. the dynamics of the number of activatable channels. Events with a higher number of participating channels will generally last longer (see below). A simple approach to elucidate this relation is to count the number of activatable channels at the beginning of each event. The distribution of this number of activatable channels is shown for three different IP3 concentrations in Fig. 4. Here we can find similar features as before: for increasing [IP3] the histogram gets skewed to the right leading to a much increased shoulder. Both the average and the standard deviation of the distribution increase with [IP3] (inset). However, the increase of the average number of activatable channels is relatively small, rising from four channels at [IP3] = 10 nM to about five channels at 80 nM. On the other hand, the variability doubles for the same range of [IP3]. Thus, it is plausible, that the increased variability determines the appearance of extended events.

Bottom Line: For increasing IP3 concentration, the release events become modulated at a timescale of minutes, with repetitive wave-like releases interspersed with several puffs.This modulation is consistent with experimental observations we present, including refractoriness and increase of puff frequency during the inter-wave interval.Our results suggest that waves are established by a random but time-modulated appearance of sustained release events, which have a high potential to trigger and synchronize activity throughout the cell.

View Article: PubMed Central - PubMed

Affiliation: Institut für Physik, Humboldt-Universität zu Berlin, Berlin, Germany.

ABSTRACT
The oscillating concentration of intracellular calcium is one of the most important examples for collective dynamics in cell biology. Localized releases of calcium through clusters of inositol 1,4,5-trisphosphate receptor channels constitute elementary signals called calcium puffs. Coupling by diffusing calcium leads to global releases and waves, but the exact mechanism of inter-cluster coupling and triggering of waves is unknown. To elucidate the relation of puffs and waves, we here model a cluster of IP3R channels using a gating scheme with variable non-equilibrium IP3 binding. Hybrid stochastic and deterministic simulations show that puffs are not stereotyped events of constant duration but are sensitive to stimulation strength and residual calcium. For increasing IP3 concentration, the release events become modulated at a timescale of minutes, with repetitive wave-like releases interspersed with several puffs. This modulation is consistent with experimental observations we present, including refractoriness and increase of puff frequency during the inter-wave interval. Our results suggest that waves are established by a random but time-modulated appearance of sustained release events, which have a high potential to trigger and synchronize activity throughout the cell.

Show MeSH