<?xml version='1.0' encoding='utf-8'?>
<!-- FILE : mazhari_model_2001_version02.xml
CREATED : 23rd May 2007
LAST MODIFIED : 23rd May 2007
AUTHOR : Catherine Lloyd
Bioengineering Institute
The University of Auckland
MODEL STATUS : This model conforms to the CellML 1.1 Specification.
DESCRIPTION : This file contains a CellML description of Mazhari et al's model of the molecular interactions between two long-QT syndrome gene products, HERG and KCNE2.
CHANGES:
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<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>Modelling HERG-KCNE2 Functional Interaction</title>
<author>
<firstname>Catherine</firstname>
<surname>Lloyd</surname>
<affiliation>
<shortaffil>Bioengineering Institute, University of Auckland</shortaffil>
</affiliation>
</author>
</articleinfo>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
The protein products of the genes <emphasis>HERG</emphasis> and <emphasis>KCNE2</emphasis> form the subunits of the rapid delayed rectifier potassium channel (I<subscript>K,r</subscript>). Mutations in KCNE2 have been associated with acquired long-QT syndrome and ventricular fibrillation, whilst mutations in the <emphasis>HERG</emphasis> gene have been associated with the inherited form of the disease. The mechansisms underlying the <emphasis>KCNE</emphasis> mutation-induced cardiac arrhythmias are not clear. An improved understanding of the functional interactions between the two gene products could facilitate the development of superior therapeutic approaches for particular lesions in either HERG or KCNE2.
</para>
<para>
In the study described here, Mazhari <emphasis>et al.</emphasis> characterise the functional effects of KCNE2 coexpression with HERG. They develop a Markov state model of both HERG and HERG-KCNE2 coassembly (see <xref linkend="fig_reaction_diagram"/> below), and use this model to elucidate mechanisms of interaction. In addition, ion channel gating models provide a quantitative description of gating behaviour and they provide clues to channel strcture. In order to predict the consequences of HERG-KCNE2 interactions for action potential repolarisation, the Markov state model was embedded within the <ulink url="${HTML_EXMPL_W_MODEL}">Winslow <emphasis>et al.</emphasis> Canine Ventricular Cell Model, 1999</ulink>.
</para>
<para>
The model has been described here in CellML (the raw CellML description of the Mazhari <emphasis>et al.</emphasis> 2001 model 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>
<ulink url="http://circres.ahajournals.org/cgi/content/abstract/89/1/33">Molecular Interactions Between Two Long-QT Syndrome Gene Products, <emphasis>HERG</emphasis> and <emphasis>KCNE2</emphasis>, Rationalized by In Vitro and In Silico Analysis</ulink>, Reza Mazhari, Joseph L. Greenstein, Raimond L. Winslow, Eduardo Marban, and H. Bradley Nuss, 2001, <ulink url="http://circres.ahajournals.org/">
<emphasis>Circulation Research</emphasis>
</ulink>, 89, 33-38. (<ulink url="http://circres.ahajournals.org/cgi/content/full/89/1/33">Full text (HTML)</ulink> and <ulink url="http://circres.ahajournals.org/cgi/reprint/89/1/33.pdf">PDF</ulink> versions of the article are available on the <emphasis>Circulation Research</emphasis> website.) <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11440975&dopt=Abstract">PubMed ID: 11440975</ulink>
</para>
<informalfigure float="0" id="fig_reaction_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>reaction diagram</title>
</objectinfo>
<imagedata fileref="mazhari_2001.png"/>
</imageobject>
</mediaobject>
<caption>State diagram of the HERG and HERG+hKCNE2 Marcov model. C<subscript>1</subscript>, C<subscript>2</subscript>, and C<subscript>3</subscript> are closed states. O is the open state, and I is the inactivated state.</caption>
</informalfigure>
<para>
While coexpression of HERG and KCNE2 alters both the kinetics and density of the ionic current, including these effects in the Winslow <emphasis>et al.</emphasis> action potential model predicts that only changes in current density significantly affect repolarisation. Therefore the main functional consequence of KCNE2 on action potential morphology is through modulation of I<subscript>K,r</subscript> density. The mutations associated with long-QT syndrome that result in only modest changes of gating kinetics may be an epiphenomena or alternatively, they may modulate action potential repoalrisation via interactions with alternative pore-forming potassium channel alpha subunits.
</para>
</sect1>
</article>
</documentation>
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<vCard:Given>Richard</vCard:Given>
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<vCard:Orgname>The University of Auckland</vCard:Orgname>
<vCard:Orgunit>The Bioengineering Institute</vCard:Orgunit>
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<rdf:Description rdf:about="rdf:#7067e84d-9959-43b5-aeae-b64db4c4fa7e">
<vCard:Given>Reza</vCard:Given>
<vCard:Family>Mazhari</vCard:Family>
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<rdf:Description rdf:about="rdf:#8e9d7333-f72a-4ad4-bacd-3d8c409d9cf9">
<dcterms:W3CDTF>2007-06-05T09:44:00+12:00</dcterms:W3CDTF>
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<dc:title>
Mazhari et al's model of the molecular interactions between two long-QT
syndrome gene products, HERG and KCNE2.
</dc:title>
<cmeta:bio_entity>cardiac myocytes</cmeta:bio_entity>
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<rdf:Description rdf:about="rdf:#a54d54ae-9bdd-4ae5-9c8d-38fcdfee6edb">
<vCard:Given>Catherine</vCard:Given>
<vCard:Family>Lloyd</vCard:Family>
<vCard:Other>May</vCard:Other>
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<rdf:Description rdf:about="/I">
<dcterms:alternative>inactivated state</dcterms:alternative>
<dc:title>I</dc:title>
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<rdf:Description rdf:about="rdf:#cf928f0c-135b-430f-bece-8008d3890829">
<vCard:Given>Catherine</vCard:Given>
<vCard:Family>Lloyd</vCard:Family>
<vCard:Other>May</vCard:Other>
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<dcterms:modified rdf:resource="rdf:#8e9d7333-f72a-4ad4-bacd-3d8c409d9cf9"/>
<rdf:value>The new version of this model has been re-coded to remove the reaction element and replace it with a simple MathML description of the model reaction kinetics. This is thought to be truer to the original publication, and information regarding the enzyme kinetics etc will later be added to the metadata through use of an ontology.
The model runs in the PCEnv simulator but gives a flat output.</rdf:value>
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<bqs:subject_type>keyword</bqs:subject_type>
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<rdf:Description rdf:about="rdf:#fd399eee-98ab-42cb-bcda-d5f0fbf26cd9">
<dc:creator rdf:resource="rdf:#7a1f72ec-87ee-495e-b1e8-87fc6dbecf17"/>
<dc:title>Molecular Interactions Between Two Long-QT Syndrome Gene Products,
HERG and KCNE2, Rationalized by In Vitro and In Silico Analysis</dc:title>
<bqs:volume>89</bqs:volume>
<bqs:first_page>33</bqs:first_page>
<bqs:Journal rdf:resource="rdf:#431dca5c-b8c4-41c3-a5d5-85682fb5d54b"/>
<dcterms:issued rdf:resource="rdf:#29249650-7e76-4c4c-b8d2-aca4908023fe"/>
<bqs:last_page>38</bqs:last_page>
</rdf:Description>
<rdf:Description rdf:about="rdf:#29249650-7e76-4c4c-b8d2-aca4908023fe">
<dcterms:W3CDTF>2001-07-06 00:00</dcterms:W3CDTF>
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<rdf:Description rdf:about="rdf:#606a537c-4113-4ca2-a08a-019c6dd7ed2c">
<vCard:N rdf:resource="rdf:#a54d54ae-9bdd-4ae5-9c8d-38fcdfee6edb"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#6681139b-251e-4e20-a1b8-93a9a3d273ab">
<vCard:FN>Catherine Lloyd</vCard:FN>
</rdf:Description>
<rdf:Description rdf:about="rdf:#f40976fb-c2a4-4016-8bf0-9adab851ad2e">
<rdf:type rdf:resource="http://www.cellml.org/bqs/1.0#Person"/>
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<rdf:Description rdf:about="rdf:#b9464b25-97fc-4c96-8987-e47b01aa001e">
<vCard:Given>H</vCard:Given>
<vCard:Family>Nuss</vCard:Family>
<vCard:Other>Bradley</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#6df9e6a2-2636-458c-925f-3207eb5b5329">
<dc:creator rdf:resource="rdf:#6681139b-251e-4e20-a1b8-93a9a3d273ab"/>
<rdf:value>This is the CellML description of Mazhari et al's model of the molecular interactions between two long-QT syndrome gene products, HERG and KCNE2.
This model can be run in PCEnv but it gives a flat output. I suspect it needs to be embedded within a whole cell model in order to give a reasonable output.</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="rdf:#f77be5a3-b7ed-469e-b577-ea26d2b88a74">
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<rdf:Description rdf:about="rdf:#d6b0066c-b6ad-4383-a422-513b7f778592">
<dcterms:W3CDTF>2003-05-23T00:00:00+00:00</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="rdf:#431dca5c-b8c4-41c3-a5d5-85682fb5d54b">
<dc:title>Circulation Research</dc:title>
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<dc:creator rdf:resource="rdf:#10d762a8-b802-4407-8710-06c70cf2a5e3"/>
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<vCard:Given>Joseph</vCard:Given>
<vCard:Family>Greenstein</vCard:Family>
<vCard:Other>L</vCard:Other>
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