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<!--  FILE :  wanant_aggregate_model_2000.xml

CREATED :  15th October 2002

LAST MODIFIED : 9th April 2003

AUTHOR :  Catherine Lloyd
          Bioengineering Institute
          The University of Auckland
          
MODEL STATUS :  This model conforms to the CellML 1.0 Specification released on
10th August 2001, and the 16/01/2002 CellML Metadata 1.0 Specification.

DESCRIPTION :  This file contains a CellML description of Wanant and Quon's
2000 aggregate model of insulin receptor binding kinetics.

CHANGES:  
  09/04/2003 - AAC - Added publication date information.  

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        <title>Insulin receptor binding kinetics: modeling and simulation studies</title>
        <author>
          <firstname>James</firstname>
          <surname>Lawson</surname>
          <affiliation>
            <shortaffil>Auckland Bioengineering Institute, The University of Auckland</shortaffil>
          </affiliation>
        </author>
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      <section id="sec_status">
        <title>Model Status</title>
        <para>
            This CellML model runs in both OpenCell and COR and represents the receptor aggregation model from the original published paper (equations 8-16). The units have been checked and they are consistent. In the absence of published initial conditions for x1-x9 arbitary values have been used. The simulation output from this model does not match the published paper.
          </para>
      </section>
      <sect1 id="sec_structure">
        <title>Model Structure</title>
        <para>
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. 
</para>
        
        <para>
The original paper reference is cited below:
</para>
        <para>
Insulin receptor binding kinetics: modeling and simulation studies, Sumanas Wanant and Michael J. Quon, 2000, <emphasis>Journal of Theoretical Biology</emphasis>, 205, 355-364.  <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=10882558&amp;dopt=Abstract">PubMed ID: 10882558</ulink>
        </para>
        
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          <caption>A schematic diagram of Wanant and Quon's 2000 receptor aggregation model.</caption>
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