- Author:
- Hanne <Hanne@hanne-nielsens-macbook.local>
- Date:
- 2009-12-15 11:08:38+13:00
- Desc:
- Added imagesi n ai and png format, removed non pub med reference
- Permanent Source URI:
- https://models.cellml.org/workspace/thomsen_neubig_1989/rawfile/eec8ddb62be079607812e1f6577b1cfc478a85f9/thomsen_neubig_1989.cellml
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<article>
<articleinfo>
<title>Model Of G-Protein Activation</title>
<author>
<firstname>James</firstname>
<surname>Laweson</surname>
<affiliation>
<shortaffil>Bioengineering Institute, University of Auckland</shortaffil>
</affiliation>
</author>
</articleinfo>
<section id="sec_status">
<title>Model Status</title>
<para>
This model has been rebuilt by James Lawson (07/06/07) using differential equations to describe the reaction kinetics rather than using reaction elements. Several parameters and initial values were also corrected from Version 01. The concentrations for D (agonist) and R (receptor) were not stated in the paper and were set to 10^-8 and 10^-9 molar (reference: Nicholas Le Novere, BioModels). This file is known to run in PCEnv and will probably run in COR, although this has not been confirmed. Because of the nature of the figures presented in the paper, it is difficult to validate the output of this model.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
G-proteins, or guanine nucleotide-binding proteins, serve to couple receptors to membrane-bound enzymes such as adenylate cyclase. In turn this induces the generation of secondary messengers such as cAMP for purposes of signal transduction. The inactive form of the G-protein consists of alpha, beta, and gamma subunits with a molecule of GDP bound to the alpha subunit. When a ligand-bound receptor interacts with the G-protein, it catalyses the exchange of GDP for GTP and activates the G-protein. The G-protein is then released from the receptor and it dissociates into separate beta-gamma and alpha-GTP (active) subunits. Active G-proteins are returned to their inactive state upon the hydrolysis of GTP to GDP by the intrinsic GTPase activity of the alpha-subunit and the alpha-GDP and beta-gamma subunits can recombine. (See the figure below).
</para>
<para>
This description of a general G-protein activation pathway is based on the mathematical model described by W.J Thomsen and R.R. Neubig in their 1989 paper. The model does not include the steps of dissociation and recombination of the alpha and beta-gamma subunits of the G-protein. In addition, it is assumed that the number of membrane bound receptors (Rt) is constant.
</para>
<para>
The complete original paper reference is cited below:
</para>
<para>
Rapid kinetics of alpha 2-adrenergic inhibition of adenylate cyclase. Evidence for a distal rate-limiting step, W.J. Thomsen and R.R. Neubig, 1989, <emphasis>Biochemistry</emphasis>, 28, 8778-8786. <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2574993&dopt=Abstract">PubMed ID: 2574993</ulink>
</para>
<informalfigure float="0" id="fig_pathway_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>the conventional rendering of a G-protein activation pathway</title>
</objectinfo>
<imagedata fileref="thomsen_neubig_1989.png"/>
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</mediaobject>
<caption>A rendering of a G-protein activation pathway.</caption>
</informalfigure>
<para>
In CellML, models are thought of as connected networks of discrete components. These components may correspond to physiologically separated regions or chemically distinct objects, or may be useful modelling abstractions. This pathway model has 17 components representing chemically distinct objects (11 chemical species and six reactions) and one component for modelling convenience in which global variables such as time are declared. The CellML rendering of the G-protein activation pathway model is shown in <xref linkend="fig_cellml_rendering"/> (the different shapes in the diagram are explained in the <ulink url="${HTML_EXMPL_GRAPHICAL_NOTATION}">notation guide</ulink>). The action of a catalyst on a reaction is again represented by dashed lines.
</para>
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<title>the cellml rendering of a G-protein activation pathway</title>
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<caption>The CellML rendering of a G-protein activation pathway.</caption>
</informalfigure>
</sect1>
</article>
</documentation>
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<rdf:value>This is the CellML description of Thomsen and Neubig's mathematical model of a G-protein activation pathway (1989).</rdf:value>
</rdf:Description>
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<ns7:simulation rdf:resource="rdf:#$sLDIm"/>
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<rdf:Description rdf:about="#thomsen_neubig_1989_version01">
<dc:title>G-protein activation pathway</dc:title>
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</rdf:Description>
<rdf:Description rdf:about="#C">
<dcterms:alternative>receptor-ligand complex</dcterms:alternative>
<dc:title>C</dc:title>
</rdf:Description>
<rdf:Description rdf:about="#L">
<dcterms:alternative>free ligand</dcterms:alternative>
<dc:title>L</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#$sLDIm">
<ns7:boundIntervals rdf:resource="rdf:#$tLDIm"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#b30c1e58-0768-479f-80a5-2e81954a240e">
<vCard:N rdf:resource="rdf:#897b445d-dabd-4ea8-8ced-b169b91f46f5"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#833b2eb7-abbe-4f93-b4bd-e59680818499">
<dcterms:W3CDTF>2007-06-07T10:41:50+12:00</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="rdf:#2e01827f-72d5-4c25-bf3c-c62f0f7512f6">
<bqs:Pubmed_id>2574993</bqs:Pubmed_id>
<bqs:JournalArticle rdf:resource="rdf:#6bb30a62-310d-4da7-bbf4-fcfc15288c0d"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#c0d4e3e3-c4ec-4d0c-b8ed-fda898eabb77">
<bqs:subject_type>keyword</bqs:subject_type>
<rdf:value>
<rdf:Bag>
<rdf:li>alpha-2-adrenoreceptor</rdf:li>
<rdf:li>signal transduction</rdf:li>
<rdf:li>adenylate cyclase</rdf:li>
<rdf:li>pharmacology</rdf:li>
</rdf:Bag>
</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="#G__GTP">
<dcterms:alternative>activated G-protein</dcterms:alternative>
<dc:title>G__GTP</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#15c67f6e-2c3f-40e9-9543-8b9c792c3d65">
<dcterms:modified rdf:resource="rdf:#8735ef6d-62ff-4237-bdf3-e3b1bffd1121"/>
<rdf:value>
Updated metadata to conform to the 16/1/02 CellML Metadata 1.0
Specification.
</rdf:value>
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</rdf:Description>
<rdf:Description rdf:about="#GTP">
<dcterms:alternative>guanosine triphosphate</dcterms:alternative>
<dc:title>GTP</dc:title>
</rdf:Description>
<rdf:Description rdf:about="#C_G_GDP">
<dcterms:alternative>receptor bound G-protein-GDP</dcterms:alternative>
<dc:title>C_G_GDP</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#897b445d-dabd-4ea8-8ced-b169b91f46f5">
<vCard:Given>Autumn</vCard:Given>
<vCard:Family>Cuellar</vCard:Family>
<vCard:Other>A.</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#d08d3967-bdb1-41ae-ad26-385c77a30967">
<dc:creator rdf:resource="rdf:#2b4163b6-78d5-4b93-91d6-5d84324a8e31"/>
<rdf:value>This model has been rebuilt by James Lawson (07/06/07) using differential equations to describe the reactions, instead of reaction elements. This model is known to run in PCEnv, and will likely run in COR as well, though this has not been tested.
Because of the nature of the figures presented in the paper, the output of this model is difficult to compare with the figures.</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="#Pi">
<dcterms:alternative>inorganic phosphate</dcterms:alternative>
<dc:title>Pi</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#57bc283a-5556-444b-b47b-06d289a5ea71">
<vCard:FN>Catherine Lloyd</vCard:FN>
</rdf:Description>
<rdf:Description rdf:about="rdf:#bbb98f91-78b5-47a5-8bf7-d6d1feb74293">
<dcterms:W3CDTF>1989-10-31</dcterms:W3CDTF>
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<vCard:Given>James</vCard:Given>
<vCard:Family>Lawson</vCard:Family>
<vCard:Other>Richard</vCard:Other>
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<rdf:Description rdf:about="rdf:#e334ac14-a08e-4045-85e6-49abd2d5dc2f">
<dc:title>Biochemistry</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#61eaefe6-4f2c-431a-8ffd-c0003d78f553">
<rdf:type rdf:resource="http://imc.org/vCard/3.0#internet"/>
<rdf:value>j.lawson@auckland.ac.nz</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="rdf:#$8XLFn1">
<rdf:rest rdf:resource="http://www.w3.org/1999/02/22-rdf-syntax-ns#nil"/>
<rdf:first rdf:resource="rdf:#$9XLFn1"/>
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<rdf:Description rdf:about="rdf:#96aa7edd-24a5-48a0-bdfc-58597344e180">
<vCard:Given>W</vCard:Given>
<vCard:Family>Thomsen</vCard:Family>
<vCard:Other>J</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#23d3084a-78b5-4b5d-afe7-21ed6e665fc9">
<vCard:ORG rdf:resource="rdf:#b493cb04-20e4-41d4-9acf-70070f7ac554"/>
<vCard:EMAIL rdf:resource="rdf:#61eaefe6-4f2c-431a-8ffd-c0003d78f553"/>
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<rdf:Description rdf:about="rdf:#d03965ca-e06a-435c-a30f-911161fb6c45">
<dcterms:modified rdf:resource="rdf:#833b2eb7-abbe-4f93-b4bd-e59680818499"/>
<rdf:value>This model has been rebuilt using differential equations to describe the reactions, instead of reaction elements.</rdf:value>
<cmeta:modifier rdf:resource="rdf:#648944e2-5aff-45ff-8266-04dff4520351"/>
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<rdf:Description rdf:about="rdf:#$tLDIm">
<rdf:rest rdf:resource="http://www.w3.org/1999/02/22-rdf-syntax-ns#nil"/>
<rdf:first rdf:resource="rdf:#$uLDIm"/>
</rdf:Description>
<rdf:Description rdf:about="#GDP">
<dcterms:alternative>guanosine diphosphate</dcterms:alternative>
<dc:title>GDP</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#4b1239dd-4ba7-43ae-b1f0-dcf2ac614b14">
<dc:subject rdf:resource="rdf:#c0d4e3e3-c4ec-4d0c-b8ed-fda898eabb77"/>
</rdf:Description>
<rdf:Description rdf:about="#C_G_GTP">
<dcterms:alternative>receptor bound G-protein-GTP</dcterms:alternative>
<dc:title>C_G_GTP</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#6bb30a62-310d-4da7-bbf4-fcfc15288c0d">
<dc:creator rdf:resource="rdf:#e4205ffa-4694-4cb4-9992-8790a3324c65"/>
<dc:title>Rapid kinetics of alpha 2-adrenergic inhibition of adenylate cyclase. Evidence for a distal rate-limiting step</dc:title>
<bqs:volume>28</bqs:volume>
<bqs:first_page>8778</bqs:first_page>
<bqs:Journal rdf:resource="rdf:#e334ac14-a08e-4045-85e6-49abd2d5dc2f"/>
<dcterms:issued rdf:resource="rdf:#bbb98f91-78b5-47a5-8bf7-d6d1feb74293"/>
<bqs:last_page>8786</bqs:last_page>
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<vCard:N rdf:resource="rdf:#6efb2017-dbcd-4bc4-bb9b-460edd3ed01c"/>
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<rdf:Description rdf:about="#G_GDP">
<dcterms:alternative>G-protein-GDP</dcterms:alternative>
<dcterms:alternative>inactivated G-protein</dcterms:alternative>
<dc:title>G_GDP</dc:title>
</rdf:Description>
<rdf:Description rdf:about="#C_G">
<dcterms:alternative>receptor bound G-protein</dcterms:alternative>
<dc:title>C_G</dc:title>
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<ns7:simulation rdf:resource="rdf:#$7XLFn1"/>
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<rdf:Description rdf:about="rdf:#$uLDIm">
<ns7:endingValue>10000</ns7:endingValue>
</rdf:Description>
<rdf:Description rdf:about="rdf:#b493cb04-20e4-41d4-9acf-70070f7ac554">
<vCard:Orgname>The University of Auckland</vCard:Orgname>
<vCard:Orgunit>The Bioengineering Research Group</vCard:Orgunit>
</rdf:Description>
<rdf:Description rdf:about="rdf:#b126d921-4aed-4ac6-b40a-a29660e8d48e">
<vCard:Given>R</vCard:Given>
<vCard:Family>Neubig</vCard:Family>
<vCard:Other>R</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#6efb2017-dbcd-4bc4-bb9b-460edd3ed01c">
<vCard:Given>James</vCard:Given>
<vCard:Family>Lawson</vCard:Family>
<vCard:Other>Richard</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#93fa8940-aba2-4a6e-9a21-272ce657d033">
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<ns7:boundIntervals rdf:resource="rdf:#$8XLFn1"/>
</rdf:Description>
</rdf:RDF>
</model>
