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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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Average event shapes of waves and puffs.To compare behavior at different [IP3] concentrations, peaks were normalized to 1. For high [IP3], event classification into waves and puffs nicely separates the termination mechanisms into fast inhibition for puffs, and a mix of inhibition and slow IP3 inactivation for waves.
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pcbi-1003965-g006: Average event shapes of waves and puffs.To compare behavior at different [IP3] concentrations, peaks were normalized to 1. For high [IP3], event classification into waves and puffs nicely separates the termination mechanisms into fast inhibition for puffs, and a mix of inhibition and slow IP3 inactivation for waves.

Mentions: To compare the temporal structure of the release events, we averaged the time courses of the number of open channels over all events for each value of [IP3]. We then normalized the average time courses for different [IP3] to a peak value of 1. Fig. 6 displays the average time courses for 10 nM and 70 nM concentrations. The solid red line shows the resulting average puff for small IP3 concentration. The fact, that for [IP3] = 10 nM we solely observed puffs, is reflected by a simple exponentially decreasing average number of open channels representing puff termination by Ca2+ inhibition on a fast time scale. However, the dotted blue line shows that for large IP3 concentration an increased second release phase appears, while for times below 200 ms no deviation from the profile of puffs occurs. Furthermore, Fig. 6 presents averaging of the same events for 70 nM concentration of IP3, but now with two groups separating into puffs and waves according to our criterion described above. The solid blue (puffs) and green (waves) curves indicate that our classification between puffs and waves worked out well, as the average event shape for puffs at [IP3] = 70 nM shows a decay very similar to that of puffs for [IP3] = 10 nM. Analyzing the event shape for waves, we can clearly distinguish the two termination mechanisms: the first 200 ms are dominated by inhibition, while afterwards the slow IP3 unbinding takes over.


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)

Average event shapes of waves and puffs.To compare behavior at different [IP3] concentrations, peaks were normalized to 1. For high [IP3], event classification into waves and puffs nicely separates the termination mechanisms into fast inhibition for puffs, and a mix of inhibition and slow IP3 inactivation for waves.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003965-g006: Average event shapes of waves and puffs.To compare behavior at different [IP3] concentrations, peaks were normalized to 1. For high [IP3], event classification into waves and puffs nicely separates the termination mechanisms into fast inhibition for puffs, and a mix of inhibition and slow IP3 inactivation for waves.
Mentions: To compare the temporal structure of the release events, we averaged the time courses of the number of open channels over all events for each value of [IP3]. We then normalized the average time courses for different [IP3] to a peak value of 1. Fig. 6 displays the average time courses for 10 nM and 70 nM concentrations. The solid red line shows the resulting average puff for small IP3 concentration. The fact, that for [IP3] = 10 nM we solely observed puffs, is reflected by a simple exponentially decreasing average number of open channels representing puff termination by Ca2+ inhibition on a fast time scale. However, the dotted blue line shows that for large IP3 concentration an increased second release phase appears, while for times below 200 ms no deviation from the profile of puffs occurs. Furthermore, Fig. 6 presents averaging of the same events for 70 nM concentration of IP3, but now with two groups separating into puffs and waves according to our criterion described above. The solid blue (puffs) and green (waves) curves indicate that our classification between puffs and waves worked out well, as the average event shape for puffs at [IP3] = 70 nM shows a decay very similar to that of puffs for [IP3] = 10 nM. Analyzing the event shape for waves, we can clearly distinguish the two termination mechanisms: the first 200 ms are dominated by inhibition, while afterwards the slow IP3 unbinding takes over.

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