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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 inter wave interval (IWI, black) and inter puff interval (IPI, blue) for different [IP3].For [IP3] = 10 nM, no waves could be observed. An IPI is defined as time between the end of the preceding and the beginning of the succeeding puff. If two puffs were split by a wave, the IPI was excluded. Error bars denote standard deviations. Inset: Similar to data from [52] there is a clear linear correlation between the average and standard deviation (SD) of the IWI. The resulting coefficient of variation is decreasing from  for [IP3] = 0.01 µM to  for [IP3] = 0.08 µM. The slope of the regression line is , the minimal average IWI (i.e., the intersection with the x-axis) is 17 s.
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pcbi-1003965-g007: Average inter wave interval (IWI, black) and inter puff interval (IPI, blue) for different [IP3].For [IP3] = 10 nM, no waves could be observed. An IPI is defined as time between the end of the preceding and the beginning of the succeeding puff. If two puffs were split by a wave, the IPI was excluded. Error bars denote standard deviations. Inset: Similar to data from [52] there is a clear linear correlation between the average and standard deviation (SD) of the IWI. The resulting coefficient of variation is decreasing from for [IP3] = 0.01 µM to for [IP3] = 0.08 µM. The slope of the regression line is , the minimal average IWI (i.e., the intersection with the x-axis) is 17 s.

Mentions: A prominent feature of our model for large [IP3] is that here puffs and waves coexist. Occurrences of waves or global oscillation require the interaction of several clusters, and this interaction may affect dynamical aspects of the release, including oscillation period and variability [53]. Nonetheless, consideration of local dynamics generally allows revealing insights into the global aspects and the local dynamics often keep a dominating influence in many oscillating systems. Thus, having distinguished waves from puffs, we now interpret the repeated occurrence of wave-like events as a slow oscillation in the local dynamics and identify the period of global oscillations by the IWI in our simulations. Fig. 7 shows averages for IWI and inter puff interval (IPI) depending on [IP3]. Similar as shown by experiments [11], our model predicts decreasing IWI for increasing [IP3]. The wave periods are generally in the same range as the periods of global oscillation measured in various cell types [11], [12], [52]. Recent experiments by Thurley et al. [55] showed exponential dependence of average period of global oscillations with stimulation, which is consistent with the scaling of IWI data in Fig. 7. Furthermore, there is a linear relation between the average and standard deviation of the IWI in our simulation results (inset). The slope of the regression line is 0.88 in simulations, which is similar to what was found for several cell types including astrocytes [26]. For HEK cells [26], [55], Hepatocytes [54] and Xenopus oocytes [4], [13], smaller variability was measured. This can possibly be understood from more complex effects of coupling, where synchronization can cause higher regularity of periodic dynamics [53].


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 inter wave interval (IWI, black) and inter puff interval (IPI, blue) for different [IP3].For [IP3] = 10 nM, no waves could be observed. An IPI is defined as time between the end of the preceding and the beginning of the succeeding puff. If two puffs were split by a wave, the IPI was excluded. Error bars denote standard deviations. Inset: Similar to data from [52] there is a clear linear correlation between the average and standard deviation (SD) of the IWI. The resulting coefficient of variation is decreasing from  for [IP3] = 0.01 µM to  for [IP3] = 0.08 µM. The slope of the regression line is , the minimal average IWI (i.e., the intersection with the x-axis) is 17 s.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003965-g007: Average inter wave interval (IWI, black) and inter puff interval (IPI, blue) for different [IP3].For [IP3] = 10 nM, no waves could be observed. An IPI is defined as time between the end of the preceding and the beginning of the succeeding puff. If two puffs were split by a wave, the IPI was excluded. Error bars denote standard deviations. Inset: Similar to data from [52] there is a clear linear correlation between the average and standard deviation (SD) of the IWI. The resulting coefficient of variation is decreasing from for [IP3] = 0.01 µM to for [IP3] = 0.08 µM. The slope of the regression line is , the minimal average IWI (i.e., the intersection with the x-axis) is 17 s.
Mentions: A prominent feature of our model for large [IP3] is that here puffs and waves coexist. Occurrences of waves or global oscillation require the interaction of several clusters, and this interaction may affect dynamical aspects of the release, including oscillation period and variability [53]. Nonetheless, consideration of local dynamics generally allows revealing insights into the global aspects and the local dynamics often keep a dominating influence in many oscillating systems. Thus, having distinguished waves from puffs, we now interpret the repeated occurrence of wave-like events as a slow oscillation in the local dynamics and identify the period of global oscillations by the IWI in our simulations. Fig. 7 shows averages for IWI and inter puff interval (IPI) depending on [IP3]. Similar as shown by experiments [11], our model predicts decreasing IWI for increasing [IP3]. The wave periods are generally in the same range as the periods of global oscillation measured in various cell types [11], [12], [52]. Recent experiments by Thurley et al. [55] showed exponential dependence of average period of global oscillations with stimulation, which is consistent with the scaling of IWI data in Fig. 7. Furthermore, there is a linear relation between the average and standard deviation of the IWI in our simulation results (inset). The slope of the regression line is 0.88 in simulations, which is similar to what was found for several cell types including astrocytes [26]. For HEK cells [26], [55], Hepatocytes [54] and Xenopus oocytes [4], [13], smaller variability was measured. This can possibly be understood from more complex effects of coupling, where synchronization can cause higher regularity of periodic dynamics [53].

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
Related in: MedlinePlus