Insulin receptor binding kinetics: modeling and simulation studies
James
Lawson
Auckland Bioengineering Institute, The University of Auckland
Model Status
This CellML model runs in both OpenCell and COR and represents the divalent receptor model from the original published paper (equations 4-7). The units have been checked and they are consistent. In the absence of published initial conditions for x1-x4 arbitary values have been used. The simulation output from this model does not match the published paper.
Model Structure
ABSTRACT: Biological actions of insulin regulate glucose metabolism and other essential physiological functions. Binding of insulin to its cell surface receptor initiates signal transduction pathways that mediate cellular responses. Thus, it is of great interest to understand the mechanisms underlying insulin receptor binding kinetics. Interestingly, negative cooperative interactions are observed at high insulin concentrations while positive cooperativity may be present at low insulin concentrations. Clearly, insulin receptor binding kinetics cannot be simply explained by a classical bimolecular reaction. Mature insulin receptors have a dimeric structure capable of binding two molecules of insulin. The binding affinity of the receptor for the second insulin molecule is significantly lower than for the first bound insulin molecule. In addition, insulin receptor aggregation occurs in response to ligand binding and aggregation may also influence binding kinetics. In this study, we develop a mathematical model for insulin receptor binding kinetics that explicitly represents the divalent nature of the insulin receptor and incorporates receptor aggregation into the kinetic model. Model parameters are based upon published data where available. Computer simulations with our model are capable of reproducing both negative and positive cooperativity at the appropriate insulin concentrations. This model may be a useful tool for helping to understand the mechanisms underlying insulin receptor binding and the coupling of receptor binding to downstream signaling events.
The original paper reference is cited below:
Insulin receptor binding kinetics: modeling and simulation studies, Sumanas Wanant and Michael J. Quon, 2000, Journal of Theoretical Biology, 205, 355-364. PubMed ID: 10882558
diagram of the divalent receptor model
A schematic diagram of Wanant and Quon's 2000 divalent receptor model.
$\frac{d \mathrm{x1}}{d \mathrm{time}}=\mathrm{k1\_}\mathrm{x3}-\mathrm{k1}\mathrm{x1}\mathrm{x2}+\mathrm{k2\_}\mathrm{x4}-\mathrm{k2}\mathrm{x1}\mathrm{x3}$
$\mathrm{scatchard}=\frac{\mathrm{x3}+\mathrm{x4}}{\mathrm{x1}}$
$\frac{d \mathrm{x2}}{d \mathrm{time}}=\mathrm{k1\_}\mathrm{x3}-\mathrm{k1}\mathrm{x1}\mathrm{x2}$
$\frac{d \mathrm{x3}}{d \mathrm{time}}=\mathrm{k1}\mathrm{x1}\mathrm{x2}-\mathrm{k1\_}\mathrm{x3}+\mathrm{k2\_}\mathrm{x4}-\mathrm{k2}\mathrm{x1}\mathrm{x3}$
$\frac{d \mathrm{x4}}{d \mathrm{time}}=\mathrm{k2}\mathrm{x1}\mathrm{x3}-\mathrm{k2\_}\mathrm{x4}$
insulin receptor
signal transduction
pharmacology
insulin
insulin receptor binding kinetics
Added publication date information.
This is the CellML description of Wanant and Quon's 2000 divalent receptor model of insulin-receptor binding kinetics.
James Lawson
James
Lawson
Richard
The University of Auckland
Auckland Bioengineering Institute
Journal of theoretical Biology
Autumn
Cuellar
A
keyword
2007-10-18T11:29:45+13:00
Sumanas
Wanant
2002-10-15T00:00:00+00:00
Catherine Lloyd
c.lloyd@auckland.ac.nz
2000-08-07
Catherine
Lloyd
May
10882558
Insulin receptor binding kinetics: modeling and simulation studies (Divalent Receptor Model)
The University of Auckland, Auckland Bioengineering Institute
2003-04-09
Fixed problem with units. Added a variable 'scatchard' in component 'insulin' which is defined by the equation: scatchard = (x3 + x4) / x1 and represents the 'bound/free' Scatchard axis.
Insulin receptor binding kinetics: modeling and simulation studies
205
355
364
Wanant and Quon's 2000 divalent receptor model of insulin-receptor binding kinetics.
Michael
Quon
J
This model has been rebuilt by James Lawson without using reaction elements, and is known to run in PCEnv, but does not currently produce the correct output. This variant corresponds to the divalent model.