- Author:
- rcai987 <devnull@localhost>
- Date:
- 2015-01-20 11:33:18+13:00
- Desc:
- Added annotations to dawson_lea_irvine_2003 model
- Permanent Source URI:
- https://models.cellml.org/workspace/dawson_lea_irvine_2003/rawfile/77728d2b6b2a7604bd73b765a2a85b77e1b24ced/dawson_lea_irvine_2003.cellml
<?xml version='1.0'?>
<!-- FILE : dawson_model3_2003.xml
CREATED : 17th October 2003
LAST MODIFIED : 17th October 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 16/1/02 CellML Metadata 1.0 Specification.
DESCRIPTION : This file contains a CellML description of Dawson et al.'s 2003 kinetic model of the inositol trisphosphate receptor.
CHANGES:
-->
<model name="dawson_lea_irvine_2003_version03" xmlns="http://www.cellml.org/cellml/1.0#" xmlns:bqs="http://www.cellml.org/bqs/1.0#" xmlns:cellml="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>Kinetic Model of the Inositol Trisphosphate Receptor</title>
<author>
<firstname>Catherine</firstname>
<surname>Lloyd</surname>
<affiliation>
<shortaffil>Bioengineering Institute, University of Auckland</shortaffil>
</affiliation>
</author>
</articleinfo>
<section id="sec_status">
<title>Model Status</title>
<para>
This model can be loaded into OpenCell without errors but can not be integrated properly.
</para>
<para>
ValidateCellML verifies this model as valid CellML with full unit consistency.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
The release of Ca<superscript>2+</superscript> from intracellular stores via InsP<subscript>3</subscript> receptors displays unusual kinetics. It has been shown that successive additions of low concentrations of InsP<subscript>3</subscript> causes successive rapid transients of Ca<superscript>2+</superscript> release. Two hypotheses have been put forward to explain this phenomenon, either:
</para>
<itemizedlist>
<listitem>
<para>Cells contain a series of Ca<superscript>2+</superscript> stores of various sensitivities to InsP<subscript>3</subscript>, such that at any given concentration of InsP<subscript>3</subscript>, only some stores will release their Ca<superscript>2+</superscript>, whilst others remain intact. This is also known as the <emphasis>all-or-nothing</emphasis> model; or </para>
</listitem>
<listitem>
<para>InsP<subscript>3</subscript> receptors are able to adapt to a particular InsP<subscript>3</subscript> concentration, such that at a given [InsP<subscript>3</subscript>], all the Ca<superscript>2+</superscript> stores partially empty. Because partial emptying induces faster cycling of Ca<superscript>2+</superscript> across the store membrane via the SERCA pump, this theory is also known as the <emphasis>steady-state</emphasis> model.</para>
</listitem>
</itemizedlist>
<para>
There are sets of experimental data in support of both explanations. The two theories require very different mechanisms. The <emphasis>all-or-nothing</emphasis> model not only requires differing sensitivities of stores to InsP<subscript>3</subscript>, but also a high degree of cooperativity such that a small range of InsP<subscript>3</subscript> concentrations will empty a particular store whilst leaving others unaffected. Differences in sensitivity could be due to structural differences, differences in InsP<subscript>3</subscript> density, intracellular cell environment, or luminal [Ca<superscript>2+</superscript>]. In contrast, the <emphasis>steady-state</emphasis> model seems to require complex, adaptive kinetic changes in the receptor. Mathematical steady-state models have been developed and in general they involve effects of Ca<superscript>2+</superscript> binding to sites within the channel or to sites in the channel mouth, although there is also evidence that the InsP<subscript>3</subscript> receptor can show adaptive behaviour.
</para>
<para>
Models of adaptive behaviour at the single channel level have been developed for the structurally homologous ryanodine receptor. It has been suggested that similar mechanisms account for the behaviour of the InsP<subscript>3</subscript> receptor. Using the Sachs <emphasis>et al.</emphasis> ryanodine receptor model as a foundation, Dawson <emphasis>et al.</emphasis> develop such a model. They begin with a relatively simple situation with no Ca<superscript>2+</superscript> fluxes (see <xref linkend="fig_reaction_diagram1"/>), to more complex situations which account for the positive and negative feedback from Ca<subscript>(cyt)</subscript>, and the inactivation of the receptor in the presence of Ca<superscript>2+</superscript> (see <xref linkend="fig_reaction_diagram2"/> and <xref linkend="fig_reaction_diagram3"/>). This final model is an adaptive model of the InsP<subscript>3</subscript> receptor that can show either <emphasis>all-or-nothing</emphasis> or <emphasis>steady-state</emphasis> behaviour, depending on the experimental conditions. The model suggests that the receptor has two interconvertible conformational states: one that rapidly binds InsP<subscript>3</subscript> but has a low affinity for the ligand, while the other state binds slowly but with a high affinity.
</para>
<para>
The models have been described here in CellML (the raw CellML description of the Dawson <emphasis>et al.</emphasis> 2003 models can be downloaded in various formats as described in <xref linkend="sec_download_this_model"/>).
</para>
<para>
The complete original paper reference is cited below:
</para>
<para>
Kinetic model of the inositol trisphosphate receptor that shows both steady-state and quantal patterns of Ca<superscript>2+</superscript> release from intracellular stores, Alan P. Dawson, Edward J. A. Lea, and Robin F. Irvine, 2003,
<emphasis>Biochemical Journal</emphasis>
, 370, 621-629. <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12479792&dopt=Abstract">PubMed ID: 12479792</ulink>
</para>
<informalfigure float="0" id="fig_reaction_diagram1">
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<title>reaction diagram1</title>
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<imagedata fileref="dawson_2003a.png"/>
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</mediaobject>
<caption>Scheme 1: An adapting model of the InsP<subscript>3</subscript> receptor.</caption>
</informalfigure>
<informalfigure float="0" id="fig_reaction_diagram2">
<mediaobject>
<imageobject>
<objectinfo>
<title>reaction diagram2</title>
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<imagedata fileref="dawson_2003b.png"/>
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</mediaobject>
<caption>Scheme 2: An adapting model of the InsP<subscript>3</subscript> receptor which includes feedback effects of Ca<superscript>2+</superscript> near the channel mouth.</caption>
</informalfigure>
<informalfigure float="0" id="fig_reaction_diagram3">
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<title>reaction diagram3</title>
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<imagedata fileref="dawson_2003c.png"/>
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<caption>Scheme 3: Adaptive channel model based on the occupation of one InsP<subscript>3</subscript> binding site being required to open the channel.</caption>
</informalfigure>
</sect1>
</article>
</documentation>
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