Limits...
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.

Show MeSH
Exemplary simulations for [IP3] = 10 nM (A-D) and [IP3] = 70 nM (E-H).In A and E the local [Ca2+] ‘line scans’ along a line on the ER membrane running through the cluster's center is shown. Warmer colors correspond to larger Ca2+ concentration and indicate the opening of channels. Because the line does not directly intersect with a channel pore, the nanodomain structure around a channel is not fully visible. The corresponding number of open channels is shown in B and F. C and G display the average concentration in the cluster vicinity (500 nm box), D and H show the number of activatable channels, i.e., the number of channels that have bound IP3 to at least three of their subunits.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4288706&req=5

pcbi-1003965-g002: Exemplary simulations for [IP3] = 10 nM (A-D) and [IP3] = 70 nM (E-H).In A and E the local [Ca2+] ‘line scans’ along a line on the ER membrane running through the cluster's center is shown. Warmer colors correspond to larger Ca2+ concentration and indicate the opening of channels. Because the line does not directly intersect with a channel pore, the nanodomain structure around a channel is not fully visible. The corresponding number of open channels is shown in B and F. C and G display the average concentration in the cluster vicinity (500 nm box), D and H show the number of activatable channels, i.e., the number of channels that have bound IP3 to at least three of their subunits.

Mentions: To check whether the domain size is sufficiently large, i.e. whether the noflux boundary conditions would significantly affect intra-cluster [Ca2+] evolution, we compared simulations of one event (first event shown in Fig. 2 G) with simulations of the same openings and closings in a much larger domain ( µm3). In these simulations (data not shown), we did not observe a significant effect of domain size on intra-cluster [Ca2+] and hence conclude that the noflux boundary conditions are a reasonable choice.


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)

Exemplary simulations for [IP3] = 10 nM (A-D) and [IP3] = 70 nM (E-H).In A and E the local [Ca2+] ‘line scans’ along a line on the ER membrane running through the cluster's center is shown. Warmer colors correspond to larger Ca2+ concentration and indicate the opening of channels. Because the line does not directly intersect with a channel pore, the nanodomain structure around a channel is not fully visible. The corresponding number of open channels is shown in B and F. C and G display the average concentration in the cluster vicinity (500 nm box), D and H show the number of activatable channels, i.e., the number of channels that have bound IP3 to at least three of their subunits.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003965-g002: Exemplary simulations for [IP3] = 10 nM (A-D) and [IP3] = 70 nM (E-H).In A and E the local [Ca2+] ‘line scans’ along a line on the ER membrane running through the cluster's center is shown. Warmer colors correspond to larger Ca2+ concentration and indicate the opening of channels. Because the line does not directly intersect with a channel pore, the nanodomain structure around a channel is not fully visible. The corresponding number of open channels is shown in B and F. C and G display the average concentration in the cluster vicinity (500 nm box), D and H show the number of activatable channels, i.e., the number of channels that have bound IP3 to at least three of their subunits.
Mentions: To check whether the domain size is sufficiently large, i.e. whether the noflux boundary conditions would significantly affect intra-cluster [Ca2+] evolution, we compared simulations of one event (first event shown in Fig. 2 G) with simulations of the same openings and closings in a much larger domain ( µm3). In these simulations (data not shown), we did not observe a significant effect of domain size on intra-cluster [Ca2+] and hence conclude that the noflux boundary conditions are a reasonable choice.

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