- Author:
- pmr2.import <nobody@models.cellml.org>
- Date:
- 2009-06-17 15:42:33+12:00
- Desc:
- committing version02 of riccobene_omann_linderman_1999
- Permanent Source URI:
- https://models.physiomeproject.org/workspace/riccobene_omann_linderman_1999/rawfile/70d5b75635857fbdf645c5ee91add3987013178e/riccobene_omann_linderman_1999.cellml
<?xml version='1.0' encoding='utf-8'?>
<!-- FILE :riccobene_model_1999.xml
CREATED : 18th 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 Riccobene, Omann and Linderman's 1999 model of the activation and desensitisation of G-protein coupled receptors.
CHANGES:
09/04/2003 - AAC - Added publication date information.
--><model xmlns="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:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bqs="http://www.cellml.org/bqs/1.0#" xmlns:cellml="http://www.cellml.org/cellml/1.0#" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" cmeta:id="riccobene_model_1999" name="riccobene_model_1999">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>A Model of Activation and Desensitisation of G-Protein Coupled Receptors</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 CellML model has been recoded to remove the reaction element. The model is known to run in both PCEnv and COR to recreate the published results. The units have been checked and are consistent.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
Signalling through G-protein coupled receptors is one of the most common and most important methods of transmitting information to the inside of cells. Many mathematical models have been published to describe this type of signal transduction, but the kinetic model described by Riccobene, Omann and Linderman (1999) is unique in that it includes the dynamics of G-protein activation and desensitisation, in addition to considering active and inactive receptor states (see the figure below). The model was used to predict how different ligands would affect the nature of the signal transduction response.
</para>
<para>
The complete original paper reference is cited below:
</para>
<para>
<ulink url="http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WMD-45FS9MH-1M&_coverDate=09%2F21%2F1999&_alid=60512469&_rdoc=1&_fmt=summary&_orig=search&_qd=1&_cdi=6932&_sort=d&_acct=C000011498&_version=1&_urlVersion=0&_userid=140507&md5=eeedd4baf8e60b260f706ae4b2e8fe60">Modeling Activation and Desensitisation of G-Protein Coupled Receptors Provides Insight into Ligand Efficacy</ulink>, Todd A. Riccobene, Geneva M. Omann and Jennifer J. Linderman, 1999 <ulink url="http://www.sciencedirect.com/science?_ob=JournalURL&_cdi=6932&_auth=y&_acct=C000011498&_version=1&_urlVersion=0&_userid=140507&md5=c8e64d20ff203cda2255f4b6b7affe4f">
<emphasis>Journal of Theoretical Biology</emphasis>
</ulink>, 200, 207-222. (A <ulink url="http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6WMD-45FS9MH-1M-1&_cdi=6932&_orig=search&_coverDate=09%2F21%2F1999&_qd=1&_sk=997999997&wchp=dGLbVlb-lSzBA&_acct=C000011498&_version=1&_userid=140507&md5=eac152447fa4c1ee1cb9479ee44b8e77&ie=f.pdf">PDF</ulink> version of the article is available for Journal Members on the Journal of Theoretical Biology website.) <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10504286&dopt=Abstract">PubMed ID: 10504286</ulink>
</para>
<informalfigure float="0" id="fig_reaction_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>diagram of the reaction pathway</title>
</objectinfo>
<imagedata fileref="riccobene_1999.png"/>
</imageobject>
</mediaobject>
<caption>A schematic diagram of Riccobene, Omann and Linderman's model of G-protein coupled receptor signalling. R is the inactive form of the receptor, R* is the active form of the receptor, R<subscript>ds</subscript> is the desensitised form of the receptor, L represents the ligand (in this case, N-formyl-norleucyl-leucyl-phenylalaninyl-nor-leucyl-tyrosyl-lysine-fluorescein, or CHO-NLFNTK-fl), G is the inactive G-protein, G* is the activated G-protein, and LR/LR*/LR<subscript>ds</subscript> represents the ligand/receptor complex in its various forms.</caption>
</informalfigure>
</sect1>
</article>
</documentation>
<units name="molar">
<unit units="mole"/>
<unit units="litre" exponent="-1"/>
</units>
<units name="first_order_rate_constant">
<unit units="second" exponent="-1"/>
</units>
<units name="second_order_rate_constant">
<unit units="molar" exponent="-1"/>
<unit units="second" exponent="-1"/>
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<variable units="second" public_interface="out" name="time"/>
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<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="R">
<dc:title>R</dc:title>
<dcterms:alternative>inactive receptor</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="molar" public_interface="out" name="R" initial_value="0.01"/>
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<ci> time </ci>
</bvar>
<ci> R </ci>
</apply>
<apply>
<minus/>
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<ci> kr </ci>
<ci> LR </ci>
</apply>
<apply>
<times/>
<apply>
<divide/>
<ci> kfR </ci>
<ci> Kact </ci>
</apply>
<ci> R_star </ci>
</apply>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci> kf </ci>
<ci> L </ci>
<ci> R </ci>
</apply>
<apply>
<times/>
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<ci> R </ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
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<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="R_star">
<dc:title>R_star</dc:title>
<dcterms:alternative>active receptor</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="molar" public_interface="out" name="R_star" initial_value="0.01"/>
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<variable units="molar" public_interface="in" name="LR_star"/>
<variable units="molar" public_interface="in" name="R"/>
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<variable units="first_order_rate_constant" public_interface="in" name="kr"/>
<variable units="first_order_rate_constant" public_interface="in" name="kfR"/>
<variable units="dimensionless" public_interface="in" name="Kact"/>
<variable units="dimensionless" public_interface="in" name="alpha"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML" id="2">
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<eq/>
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<diff/>
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<ci> time </ci>
</bvar>
<ci> R_star </ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci> kr </ci>
<ci> LR_star </ci>
</apply>
<apply>
<times/>
<ci> kfR </ci>
<ci> R </ci>
</apply>
</apply>
<apply>
<plus/>
<apply>
<times/>
<ci> alpha </ci>
<ci> kf </ci>
<ci> L </ci>
<ci> R_star </ci>
</apply>
<apply>
<times/>
<apply>
<divide/>
<ci> kfR </ci>
<ci> Kact </ci>
</apply>
<ci> R_star </ci>
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</apply>
</apply>
</math>
</component>
<component cmeta:id="LR" name="LR">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="LR">
<dc:title>LR</dc:title>
<dcterms:alternative>inactive ligand-receptor complex</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="molar" public_interface="out" name="LR" initial_value="0.01"/>
<variable units="molar" public_interface="in" name="L"/>
<variable units="molar" public_interface="in" name="R"/>
<variable units="molar" public_interface="in" name="LR_star"/>
<variable units="second_order_rate_constant" public_interface="in" name="kf"/>
<variable units="first_order_rate_constant" public_interface="in" name="kr"/>
<variable units="first_order_rate_constant" public_interface="in" name="kfR"/>
<variable units="dimensionless" public_interface="in" name="Kact"/>
<variable units="dimensionless" public_interface="in" name="alpha"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML" id="3">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> LR </ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci> kf </ci>
<ci> L </ci>
<ci> R </ci>
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<apply>
<times/>
<apply>
<divide/>
<ci> kfR </ci>
<apply>
<times/>
<ci> alpha </ci>
<ci> Kact </ci>
</apply>
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<ci> LR_star </ci>
</apply>
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<ci> kr </ci>
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<ci> kfR </ci>
<ci> LR </ci>
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<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="LR_star">
<dc:title>LR_star</dc:title>
<dcterms:alternative>active ligand-receptor complex</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="molar" public_interface="out" name="LR_star" initial_value="0.01"/>
<variable units="molar" public_interface="in" name="L"/>
<variable units="molar" public_interface="in" name="R_star"/>
<variable units="molar" public_interface="in" name="LR"/>
<variable units="second_order_rate_constant" public_interface="in" name="kf"/>
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<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML" id="4">
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<ci> time </ci>
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<ci> LR_star </ci>
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<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci> kfR </ci>
<ci> LR </ci>
</apply>
<apply>
<times/>
<ci> alpha </ci>
<ci> kf </ci>
<ci> L </ci>
<ci> R_star </ci>
</apply>
</apply>
<apply>
<plus/>
<apply>
<times/>
<apply>
<divide/>
<ci> kfR </ci>
<apply>
<times/>
<ci> alpha </ci>
<ci> Kact </ci>
</apply>
</apply>
<ci> LR_star </ci>
</apply>
<apply>
<times/>
<ci> kds </ci>
<ci> LR_star </ci>
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<apply>
<times/>
<ci> kr </ci>
<ci> LR_star </ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component cmeta:id="LR_ds" name="LR_ds">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="LR_ds">
<dc:title>LR_ds</dc:title>
<dcterms:alternative>desensitised ligand-receptor complex</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="molar" public_interface="out" name="LR_ds" initial_value="0.01"/>
<variable units="molar" public_interface="in" name="LR_star"/>
<variable units="molar" public_interface="in" name="R_ds"/>
<variable units="molar" public_interface="in" name="L"/>
<variable units="second_order_rate_constant" public_interface="in" name="kf2"/>
<variable units="first_order_rate_constant" public_interface="in" name="kr2"/>
<variable units="first_order_rate_constant" public_interface="in" name="kds"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML" id="5">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> LR_ds </ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci> kds </ci>
<ci> LR_star </ci>
</apply>
<apply>
<times/>
<ci> kf2 </ci>
<ci> L </ci>
<ci> R_ds </ci>
</apply>
</apply>
<apply>
<times/>
<ci> kr2 </ci>
<ci> LR_ds </ci>
</apply>
</apply>
</apply>
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</component>
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<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="R_ds">
<dc:title>R_ds</dc:title>
<dcterms:alternative>desensitised receptor </dcterms:alternative>
</rdf:Description>
</rdf:RDF>
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<variable units="molar" public_interface="in" name="LR_ds"/>
<variable units="molar" public_interface="in" name="L"/>
<variable units="second_order_rate_constant" public_interface="in" name="kf2"/>
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<math xmlns="http://www.w3.org/1998/Math/MathML" id="6">
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<ci> time </ci>
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<ci> R_ds </ci>
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<apply>
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<ci> kr2 </ci>
<ci> LR_ds </ci>
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<apply>
<times/>
<ci> kf2 </ci>
<ci> L </ci>
<ci> R_ds </ci>
</apply>
</apply>
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<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="G_star">
<dc:title>G_star</dc:title>
<dcterms:alternative>activated G-protein</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="molar" public_interface="out" name="G_star" initial_value="0.01"/>
<variable units="molar" public_interface="in" name="LR_star"/>
<variable units="molar" public_interface="in" name="R_star"/>
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<variable units="second_order_rate_constant" public_interface="in" name="ka"/>
<variable units="first_order_rate_constant" public_interface="in" name="ki"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML" id="7">
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<eq/>
<apply>
<diff/>
<bvar>
<ci> time </ci>
</bvar>
<ci> G_star </ci>
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<apply>
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<ci> ka </ci>
<ci> G </ci>
<apply>
<plus/>
<ci> LR_star </ci>
<ci> R_star </ci>
</apply>
</apply>
<apply>
<times/>
<ci> ki </ci>
<ci> G_star </ci>
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<dc:title>G</dc:title>
<dcterms:alternative>inactive G-protein</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
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<variable units="molar" public_interface="in" name="LR_star"/>
<variable units="molar" public_interface="in" name="R_star"/>
<variable units="molar" public_interface="in" name="G_star"/>
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<ci> time </ci>
</bvar>
<ci> G </ci>
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<ci> G </ci>
<apply>
<plus/>
<ci> LR_star </ci>
<ci> R_star </ci>
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</apply>
</apply>
</apply>
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<dc:title>L</dc:title>
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</rdf:Description>
</rdf:RDF>
<variable units="molar" public_interface="out" name="L" initial_value="1E-12"/>
</component>
<component name="model_parameters">
<variable units="first_order_rate_constant" public_interface="out" name="kr" initial_value="0.37"/>
<variable units="second_order_rate_constant" public_interface="out" name="kf" initial_value="8.4E7"/>
<variable units="first_order_rate_constant" public_interface="out" name="kr2" initial_value="4.6E-3"/>
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<variable units="first_order_rate_constant" public_interface="out" name="kfR" initial_value="10"/>
<variable units="second_order_rate_constant" public_interface="out" name="ka" initial_value="1E-7"/>
<variable units="first_order_rate_constant" public_interface="out" name="ki" initial_value="2E-1"/>
<variable units="dimensionless" public_interface="out" name="Kact" initial_value="1E-4"/>
<variable units="dimensionless" public_interface="out" name="alpha" initial_value="1E1"/>
</component>
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<map_components component_2="environment" component_1="LR"/>
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<connection>
<map_components component_2="environment" component_1="LR_ds"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="R_ds"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="G_star"/>
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</connection>
<connection>
<map_components component_2="environment" component_1="G"/>
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</connection>
<connection>
<map_components component_2="L" component_1="R"/>
<map_variables variable_2="L" variable_1="L"/>
</connection>
<connection>
<map_components component_2="LR" component_1="R"/>
<map_variables variable_2="LR" variable_1="LR"/>
<map_variables variable_2="R" variable_1="R"/>
</connection>
<connection>
<map_components component_2="R_star" component_1="R"/>
<map_variables variable_2="R" variable_1="R"/>
<map_variables variable_2="R_star" variable_1="R_star"/>
</connection>
<connection>
<map_components component_2="model_parameters" component_1="R"/>
<map_variables variable_2="kf" variable_1="kf"/>
<map_variables variable_2="kr" variable_1="kr"/>
<map_variables variable_2="kfR" variable_1="kfR"/>
<map_variables variable_2="Kact" variable_1="Kact"/>
</connection>
<connection>
<map_components component_2="L" component_1="R_star"/>
<map_variables variable_2="L" variable_1="L"/>
</connection>
<connection>
<map_components component_2="LR_star" component_1="R_star"/>
<map_variables variable_2="LR_star" variable_1="LR_star"/>
<map_variables variable_2="R_star" variable_1="R_star"/>
</connection>
<connection>
<map_components component_2="model_parameters" component_1="R_star"/>
<map_variables variable_2="kf" variable_1="kf"/>
<map_variables variable_2="kr" variable_1="kr"/>
<map_variables variable_2="kfR" variable_1="kfR"/>
<map_variables variable_2="Kact" variable_1="Kact"/>
<map_variables variable_2="alpha" variable_1="alpha"/>
</connection>
<connection>
<map_components component_2="L" component_1="LR"/>
<map_variables variable_2="L" variable_1="L"/>
</connection>
<connection>
<map_components component_2="LR_star" component_1="LR"/>
<map_variables variable_2="LR" variable_1="LR"/>
<map_variables variable_2="LR_star" variable_1="LR_star"/>
</connection>
<connection>
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