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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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(A) Gating scheme of the modified DYK model used to model the states of a single subunit. The transition rates are determined by [Ca2+] and [IP3] here denoted by  and , respectively, and the  and  as given in Table 1. (B) Steady state open probability of the modified DYK model for a single channel. For increasing [IP3], the open probability increases and the maximum of the open probability shifts to higher [Ca2+].
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pcbi-1003965-g001: (A) Gating scheme of the modified DYK model used to model the states of a single subunit. The transition rates are determined by [Ca2+] and [IP3] here denoted by and , respectively, and the and as given in Table 1. (B) Steady state open probability of the modified DYK model for a single channel. For increasing [IP3], the open probability increases and the maximum of the open probability shifts to higher [Ca2+].

Mentions: The open and close dynamics of IP3R channels are incorporated via a modified DeYoung-Keizer (DYK) model [38], [39]. Here, an IP3R channel consists of four identical subunits, where each subunit possesses three different binding sites: An activating site for Ca2+, an inhibiting Ca2+ site, and an IP3 binding site. Hence, a subunit can undergo transitions between eight different states X (see Fig. 1 A). The index indicates the state of the IP3 site, the one of the activating Ca2+ site and the state of the inhibiting Ca2+ site. An index is 1 if Ca2+ or IP3 are bound and 0 if not. A channel is defined to be open if at least three of the four subunits are in the state X110[15]. The parameters defining the transition rates of the model were fitted to patch-clamp data for type 1 IP3R channels in [28], [40], [41] and are given in Table 1. These rates have been chosen at values similar to our earlier publication [27] except for (and consequently ), which has been adjusted by a factor of about 3 to reflect a large shift in open probability in dependence on [IP3]. In order to obey detailed balance, these parameters have to satisfy the following condition:(1)This relation is crucial for the unbinding dynamics of IP3 that we will report on below [27].


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)

(A) Gating scheme of the modified DYK model used to model the states of a single subunit. The transition rates are determined by [Ca2+] and [IP3] here denoted by  and , respectively, and the  and  as given in Table 1. (B) Steady state open probability of the modified DYK model for a single channel. For increasing [IP3], the open probability increases and the maximum of the open probability shifts to higher [Ca2+].
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003965-g001: (A) Gating scheme of the modified DYK model used to model the states of a single subunit. The transition rates are determined by [Ca2+] and [IP3] here denoted by and , respectively, and the and as given in Table 1. (B) Steady state open probability of the modified DYK model for a single channel. For increasing [IP3], the open probability increases and the maximum of the open probability shifts to higher [Ca2+].
Mentions: The open and close dynamics of IP3R channels are incorporated via a modified DeYoung-Keizer (DYK) model [38], [39]. Here, an IP3R channel consists of four identical subunits, where each subunit possesses three different binding sites: An activating site for Ca2+, an inhibiting Ca2+ site, and an IP3 binding site. Hence, a subunit can undergo transitions between eight different states X (see Fig. 1 A). The index indicates the state of the IP3 site, the one of the activating Ca2+ site and the state of the inhibiting Ca2+ site. An index is 1 if Ca2+ or IP3 are bound and 0 if not. A channel is defined to be open if at least three of the four subunits are in the state X110[15]. The parameters defining the transition rates of the model were fitted to patch-clamp data for type 1 IP3R channels in [28], [40], [41] and are given in Table 1. These rates have been chosen at values similar to our earlier publication [27] except for (and consequently ), which has been adjusted by a factor of about 3 to reflect a large shift in open probability in dependence on [IP3]. In order to obey detailed balance, these parameters have to satisfy the following condition:(1)This relation is crucial for the unbinding dynamics of IP3 that we will report on below [27].

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