A Dynamic Model Of The Type-2 Inositol Triphosphate Receptor
Catherine
Lloyd
Auckland Bioengineering Institute, The University of Auckland
Model Status
This CellML model runs in OpenCell and COR and the units are consistent throughout. The model runs to recreate published results and is currently configured to recreate Figure 4 (Lower Plot, Trace 4), but variation of the IP3 and Calcium concentrations will allow the model to recreate different figures.
Model Structure
ABSTRACT: The dynamic properties of the inositol (1,4,5)-trisphosphate (IP(3)) receptor are crucial for the control of intracellular Ca(2+), including the generation of Ca(2+) oscillations and waves. However, many models of this receptor do not agree with recent experimental data on the dynamic responses of the receptor. We construct a model of the IP(3) receptor and fit the model to dynamic and steady-state experimental data from type-2 IP(3) receptors. Our results indicate that, (i) Ca(2+) binds to the receptor using saturating, not mass-action, kinetics; (ii) Ca(2+) decreases the rate of IP(3) binding while simultaneously increasing the steady-state sensitivity of the receptor to IP(3); (iii) the rate of Ca(2+)-induced receptor activation increases with Ca(2+) and is faster than Ca(2+)-induced receptor inactivation; and (iv) IP(3) receptors are sequentially activated and inactivated by Ca(2+) even when IP(3) is bound. Our results emphasize that measurement of steady-state properties alone is insufficient to characterize the functional properties of the receptor.
The original paper reference is cited below:
A dynamic model of the type-2 inositol triphosphate receptor, James Sneyd and Jean-Francois Dufour, 2002, Proceedings of the National Academy of Sciences , 99, 2398-2403. PubMed ID: 11842185
A simplified diagram of the IPR model
A simplified diagram of the IPR model, where R represents the free receptor, O is the open state of the channel, A is the activated state of the channel and I1, I2, and S are three inactive states.
$\frac{d R}{d \mathrm{time}}=\mathrm{phi\_2b}O+(\mathrm{k\_1b}+\mathrm{l\_2b})\mathrm{I\_1}-\mathrm{phi\_2}pR+\mathrm{phi\_1}R$
$\frac{d O}{d \mathrm{time}}=\mathrm{phi\_2}pR+\mathrm{phi\_4b}A+\mathrm{k\_3b}S-(\mathrm{phi\_2b}+\mathrm{phi\_4}+1\mathrm{phi\_3})O$
$S=1-R+O+A+\mathrm{I\_1}+\mathrm{I\_2}$
$\frac{d \mathrm{I\_1}}{d \mathrm{time}}=\mathrm{phi\_1}R-(\mathrm{k\_1b}+\mathrm{l\_2b})\mathrm{I\_1}$
$\frac{d \mathrm{I\_2}}{d \mathrm{time}}=\mathrm{phi\_5}A-(\mathrm{k\_1b}+\mathrm{l\_2b})\mathrm{I\_2}$
$\frac{d A}{d \mathrm{time}}=\mathrm{phi\_4}O+(\mathrm{k\_1b}+\mathrm{l\_2b})\mathrm{I\_2}-\mathrm{phi\_4b}A+\mathrm{phi\_5}A$
$\mathrm{open\_probability}=(0.1O+0.9A)^{4}$
$\mathrm{phi\_1}=\frac{(\mathrm{k\_1a}\mathrm{L\_1}+\mathrm{l\_2a})c}{\mathrm{L\_1}+c(1+\frac{\mathrm{L\_1}}{\mathrm{L\_3}})}\mathrm{phi\_2}=\frac{\mathrm{k\_2a}\mathrm{L\_3}+\mathrm{l\_4a}c}{\mathrm{L\_3}+c(1+\frac{\mathrm{L\_3}}{\mathrm{L\_1}})}\mathrm{phi\_2b}=\frac{\mathrm{k\_2b}+\mathrm{l\_4b}c}{1+\frac{c}{\mathrm{L\_5}}}\mathrm{phi\_3}=\frac{\mathrm{k\_3a}\mathrm{L\_5}}{c+\mathrm{L\_5}}\mathrm{phi\_4}=\frac{(\mathrm{k\_4a}\mathrm{L\_5}+\mathrm{l\_6a})c}{c+\mathrm{L\_5}}\mathrm{phi\_4b}=\frac{\mathrm{L\_1}(\mathrm{k\_4b}+\mathrm{l\_6b})}{c+\mathrm{L\_1}}\mathrm{phi\_5}=\frac{(\mathrm{k\_1a}\mathrm{L\_1}+\mathrm{l\_2a})c}{c+\mathrm{L\_1}}$
A dynamic model of the type-2 inositol triphosphate receptor99240323982007-06-05T10:45:11+12:00Jean-FrancoisDufourkeyword1.5100000.1Catherine LloydCorrected two of the equations.CatherineLloydMay11842185OOpen stateThe University of Auckland, Auckland Bioengineering InstituteI_1Inactive state 2This is the CellML description of Sneyd and Dufour's 2002 dynamic model of type-2 inositol triphosphate receptor. The dynamic properties of this receptor are essential for the control of intracellular calcium, including the generation of calcium oscillations and waves.2007-05-24T08:10:03+12:00calcium dynamicsIP3 receptor2007-05-22T00:00:00+00:00AActive statePNASAuckland Bioengineering InstituteThe University of Auckland2002-02-19CatherineLloydMayJamesSneydCatherineLloydMayRReceptorI_1Inactive state 1The new version of this model has been re-coded to remove the reaction element and replace it with a simple MathML description of the model reaction kinetics. This is thought to be truer to the original publication, and information regarding the enzyme kinetics etc will later be added to the metadata through use of an ontology. The model runs in the PCEnv simulator and gives a nice curved output.c.lloyd@auckland.ac.nz
The Sneyd-Dufour 2002 dynamic model of the type-2 inositol triphosphate receptor.
SShut state