- Author:
- pmr2.import <nobody@models.cellml.org>
- Date:
- 2006-07-09 08:02:12+12:00
- Desc:
- committing version01 of mazhari_greenstein_winslow_marban_nuss_2001
- Permanent Source URI:
- https://staging.physiomeproject.org/workspace/mazhari_greenstein_winslow_marban_nuss_2001/rawfile/5d1471d7fe6c6591b95b7c652d253085d02e8b63/mazhari_greenstein_winslow_marban_nuss_2001.cellml
<?xml version='1.0' encoding='utf-8'?>
<!-- FILE : mazhari_model_2001.xml
CREATED : 16th May 2003
LAST MODIFIED : 16th May 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 Mazhari et al's model of the molecular interactions between two long-QT syndrome gene products, HERG and KCNE2.
CHANGES:
--><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="mazhari_greenstein_winslow_marban_nuss_2001_version01" name="mazhari_greenstein_winslow_marban_nuss_2001_version01">
<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>
<section id="sec_status">
<title>Model Status</title>
<para>
This is the original unchecked version of the model imported from the previous
CellML model repository, 24-Jan-2006.
</para>
</section>
<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>
<!--
Below, we define some additional units for association with variables and
constants within the model.
-->
<units name="millivolt">
<unit units="volt" prefix="milli"/>
</units>
<units name="micromolar">
<unit units="mole" prefix="micro"/>
<unit units="litre" exponent="-1"/>
</units>
<units name="flux">
<unit units="micromolar"/>
<unit units="second" exponent="-1"/>
</units>
<units name="first_order_rate_constant">
<unit units="second" exponent="-1"/>
</units>
<units name="second_order_rate_constant">
<unit units="micromolar" exponent="-1"/>
<unit units="second" exponent="-1"/>
</units>
<!--
The "environment" component is used to declare variables that are used by
all or most of the other components, in this case just "time".
-->
<component name="environment">
<variable units="second" public_interface="out" name="time"/>
</component>
<component name="membrane">
<variable units="millivolt" public_interface="out" name="Vm"/>
</component>
<!--
The following components describe all the reactants and products involved in
reactions.
-->
<component name="C1" cmeta:id="C1">
<variable units="micromolar" public_interface="out" name="C1"/>
<variable units="flux" public_interface="in" name="delta_C1_rxn_1"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>C1</ci>
</apply>
<ci>delta_C1_rxn_1</ci>
</apply>
</math>
</component>
<component name="C2" cmeta:id="C2">
<variable units="micromolar" public_interface="out" name="C2"/>
<variable units="flux" public_interface="in" name="delta_C2_rxn_1"/>
<variable units="flux" public_interface="in" name="delta_C2_rxn_2"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>C2</ci>
</apply>
<apply>
<plus/>
<ci>delta_C2_rxn_1</ci>
<ci>delta_C2_rxn_2</ci>
</apply>
</apply>
</math>
</component>
<component name="C3" cmeta:id="C3">
<variable units="micromolar" public_interface="out" name="C3"/>
<variable units="flux" public_interface="in" name="delta_C3_rxn_2"/>
<variable units="flux" public_interface="in" name="delta_C3_rxn_3"/>
<variable units="flux" public_interface="in" name="delta_C3_rxn_5"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>C3</ci>
</apply>
<apply>
<plus/>
<ci>delta_C3_rxn_2</ci>
<ci>delta_C3_rxn_3</ci>
<ci>delta_C3_rxn_5</ci>
</apply>
</apply>
</math>
</component>
<component name="O" cmeta:id="O">
<variable units="micromolar" public_interface="out" name="O"/>
<variable units="flux" public_interface="in" name="delta_O_rxn_4"/>
<variable units="flux" public_interface="in" name="delta_O_rxn_5"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>O</ci>
</apply>
<apply>
<plus/>
<ci>delta_O_rxn_4</ci>
<ci>delta_O_rxn_5</ci>
</apply>
</apply>
</math>
</component>
<component name="I" cmeta:id="I">
<variable units="micromolar" public_interface="out" name="I"/>
<variable units="flux" public_interface="in" name="delta_I_rxn_3"/>
<variable units="flux" public_interface="in" name="delta_I_rxn_4"/>
<variable units="second" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>I</ci>
</apply>
<apply>
<plus/>
<ci>delta_I_rxn_3</ci>
<ci>delta_I_rxn_4</ci>
</apply>
</apply>
</math>
</component>
<!--
The following components describe the reactions of the model.
-->
<component name="reaction1">
<variable units="micromolar" public_interface="in" name="C1"/>
<variable units="micromolar" public_interface="in" name="C2"/>
<variable units="millivolt" public_interface="in" name="Vm"/>
<variable units="first_order_rate_constant" name="alpha0"/>
<variable units="first_order_rate_constant" name="beta0"/>
<variable units="flux" public_interface="out" name="delta_C1_rxn_1"/>
<variable units="flux" public_interface="out" name="delta_C2_rxn_1"/>
<variable units="flux" name="r"/>
<reaction reversible="yes">
<variable_ref variable="C1">
<role stoichiometry="1" direction="forward" delta_variable="delta_C1_rxn_1" role="reactant"/>
</variable_ref>
<variable_ref variable="C2">
<role stoichiometry="1" direction="forward" delta_variable="delta_C2_rxn_1" role="product"/>
</variable_ref>
<variable_ref variable="r">
<role role="rate">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> r </ci>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<times/>
<ci> alpha0 </ci>
<ci> C1 </ci>
</apply>
</apply>
<apply>
<times/>
<ci> beta0 </ci>
<ci> C2 </ci>
</apply>
</apply>
</apply>
</math>
</role>
</variable_ref>
</reaction>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="alpha0_calculation">
<eq/>
<ci> alpha0 </ci>
<apply>
<times/>
<cn cellml:units="first_order_rate_constant"> 0.0069 </cn>
<apply>
<exp/>
<apply>
<times/>
<cn cellml:units="dimensionless"> 0.0272 </cn>
<ci> Vm </ci>
</apply>
</apply>
</apply>
</apply>
<apply id="beta0_calculation">
<eq/>
<ci> beta0 </ci>
<apply>
<times/>
<cn cellml:units="first_order_rate_constant"> 0.0227 </cn>
<apply>
<exp/>
<apply>
<times/>
<cn cellml:units="dimensionless"> -0.0431 </cn>
<ci> Vm </ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="reaction2">
<variable units="micromolar" public_interface="in" name="C2"/>
<variable units="micromolar" public_interface="in" name="C3"/>
<variable units="first_order_rate_constant" name="Kf" initial_value="0.0266"/>
<variable units="first_order_rate_constant" name="Kb" initial_value="0.1348"/>
<variable units="flux" public_interface="out" name="delta_C2_rxn_2"/>
<variable units="flux" public_interface="out" name="delta_C3_rxn_2"/>
<variable units="flux" name="r"/>
<reaction reversible="yes">
<variable_ref variable="C2">
<role stoichiometry="1" direction="forward" delta_variable="delta_C2_rxn_2" role="reactant"/>
</variable_ref>
<variable_ref variable="C3">
<role stoichiometry="1" direction="forward" delta_variable="delta_C3_rxn_2" role="product"/>
</variable_ref>
<variable_ref variable="r">
<role role="rate">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> r </ci>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<times/>
<ci> Kf </ci>
<ci> C2 </ci>
</apply>
</apply>
<apply>
<times/>
<ci> Kb </ci>
<ci> C3 </ci>
</apply>
</apply>
</apply>
</math>
</role>
</variable_ref>
</reaction>
</component>
<component name="reaction3">
<variable units="micromolar" public_interface="in" name="C3"/>
<variable units="micromolar" public_interface="in" name="I"/>
<variable units="millivolt" public_interface="in" name="Vm"/>
<variable units="first_order_rate_constant" name="alphai3"/>
<variable units="first_order_rate_constant" public_interface="out" name="alphai"/>
<variable units="first_order_rate_constant" public_interface="out" name="alpha1"/>
<variable units="first_order_rate_constant" public_interface="out" name="betai"/>
<variable units="first_order_rate_constant" public_interface="out" name="beta1"/>
<variable units="first_order_rate_constant" name="psi"/>
<variable units="flux" public_interface="out" name="delta_C3_rxn_3"/>
<variable units="flux" public_interface="out" name="delta_I_rxn_3"/>
<variable units="flux" name="r"/>
<reaction reversible="yes">
<variable_ref variable="C3">
<role stoichiometry="1" direction="forward" delta_variable="delta_C3_rxn_3" role="reactant"/>
</variable_ref>
<variable_ref variable="I">
<role stoichiometry="1" direction="forward" delta_variable="delta_I_rxn_3" role="product"/>
</variable_ref>
<variable_ref variable="r">
<role role="rate">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> r </ci>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<times/>
<ci> alphai3 </ci>
<ci> C3 </ci>
</apply>
</apply>
<apply>
<times/>
<ci> psi </ci>
<ci> I </ci>
</apply>
</apply>
</apply>
</math>
</role>
</variable_ref>
</reaction>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply id="psi_calculation">
<eq/>
<ci> psi </ci>
<apply>
<divide/>
<apply>
<times/>
<ci> beta1 </ci>
<ci> betai </ci>
<ci> alphai3 </ci>
</apply>
<apply>
<times/>
<ci> alpha1 </ci>
<ci> alphai </ci>
</apply>
</apply>
</apply>
<apply id="beta1_calculation">
<eq/>
<ci> beta1 </ci>
<apply>
<times/>
<cn cellml:units="first_order_rate_constant"> 0.0009 </cn>
<apply>
<exp/>
<apply>
<times/>
<cn cellml:units="dimensionless"> -0.0269 </cn>
<ci> Vm </ci>
</apply>
</apply>
</apply>
</apply>
<apply id="alpha1_calculation">
<eq/>
<ci> alpha1 </ci>
<apply>
<times/>
<cn cellml:units="first_order_rate_constant"> 0.0218 </cn>
<apply>
<exp/>
<apply>
<times/>
<cn cellml:units="dimensionless"> 0.0262 </cn>
<ci> Vm </ci>
</apply>
</apply>
</apply>
</apply>
<apply id="betai_calculation">
<eq/>
<ci> betai </ci>
<apply>
<times/>
<cn cellml:units="first_order_rate_constant"> 0.0059 </cn>
<apply>
<exp/>
<apply>
<times/>
<cn cellml:units="dimensionless"> -0.0443 </cn>
<ci> Vm </ci>
</apply>
</apply>
</apply>
</apply>
<apply id="alphai_calculation">
<eq/>
<ci> alphai </ci>
<apply>
<times/>
<cn cellml:units="first_order_rate_constant"> 0.0622 </cn>
<apply>
<exp/>
<apply>
<times/>
<cn cellml:units="dimensionless"> 0.0120 </cn>
<ci> Vm </ci>
</apply>
</apply>
</apply>
</apply>
<apply id="alphai3_calculation">
<eq/>
<ci> alphai3 </ci>
<apply>
<times/>
<cn cellml:units="first_order_rate_constant"> 1.29E-5 </cn>
<apply>
<exp/>
<apply>
<times/>
<cn cellml:units="dimensionless"> 2.71E-6 </cn>
<ci> Vm </ci>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component name="reaction4">
<variable units="micromolar" public_interface="in" name="I"/>
<variable units="micromolar" public_interface="in" name="O"/>
<variable units="first_order_rate_constant" public_interface="in" name="alphai"/>
<variable units="first_order_rate_constant" public_interface="in" name="betai"/>
<variable units="flux" public_interface="out" name="delta_I_rxn_4"/>
<variable units="flux" public_interface="out" name="delta_O_rxn_4"/>
<variable units="flux" name="r"/>
<reaction reversible="yes">
<variable_ref variable="I">
<role stoichiometry="1" direction="forward" delta_variable="delta_I_rxn_4" role="reactant"/>
</variable_ref>
<variable_ref variable="O">
<role stoichiometry="1" direction="forward" delta_variable="delta_O_rxn_4" role="product"/>
</variable_ref>
<variable_ref variable="r">
<role role="rate">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> r </ci>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<times/>
<ci> betai </ci>
<ci> I </ci>
</apply>
</apply>
<apply>
<times/>
<ci> alphai </ci>
<ci> O </ci>
</apply>
</apply>
</apply>
</math>
</role>
</variable_ref>
</reaction>
</component>
<component name="reaction5">
<variable units="micromolar" public_interface="in" name="C3"/>
<variable units="micromolar" public_interface="in" name="O"/>
<variable units="first_order_rate_constant" public_interface="in" name="beta1"/>
<variable units="first_order_rate_constant" public_interface="in" name="alpha1"/>
<variable units="flux" public_interface="out" name="delta_C3_rxn_5"/>
<variable units="flux" public_interface="out" name="delta_O_rxn_5"/>
<variable units="flux" name="r"/>
<reaction reversible="yes">
<variable_ref variable="C3">
<role stoichiometry="1" direction="forward" delta_variable="delta_C3_rxn_5" role="reactant"/>
</variable_ref>
<variable_ref variable="O">
<role stoichiometry="1" direction="forward" delta_variable="delta_O_rxn_5" role="product"/>
</variable_ref>
<variable_ref variable="r">
<role role="rate">
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> r </ci>
<apply>
<plus/>
<apply>
<minus/>
<apply>
<times/>
<ci> alpha1 </ci>
<ci> C3 </ci>
</apply>
</apply>
<apply>
<times/>
<ci> beta1 </ci>
<ci> O </ci>
</apply>
</apply>
</apply>
</math>
</role>
</variable_ref>
</reaction>
</component>
<connection>
<map_components component_2="environment" component_1="C1"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="C2"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="C3"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="O"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="I"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="membrane" component_1="reaction1"/>
<map_variables variable_2="Vm" variable_1="Vm"/>
</connection>
<connection>
<map_components component_2="membrane" component_1="reaction3"/>
<map_variables variable_2="Vm" variable_1="Vm"/>
</connection>
<connection>
<map_components component_2="reaction1" component_1="C1"/>
<map_variables variable_2="C1" variable_1="C1"/>
<map_variables variable_2="delta_C1_rxn_1" variable_1="delta_C1_rxn_1"/>
</connection>
<connection>
<map_components component_2="reaction1" component_1="C2"/>
<map_variables variable_2="C2" variable_1="C2"/>
<map_variables variable_2="delta_C2_rxn_1" variable_1="delta_C2_rxn_1"/>
</connection>
<connection>
<map_components component_2="reaction2" component_1="C2"/>
<map_variables variable_2="C2" variable_1="C2"/>
<map_variables variable_2="delta_C2_rxn_2" variable_1="delta_C2_rxn_2"/>
</connection>
<connection>
<map_components component_2="reaction2" component_1="C3"/>
<map_variables variable_2="C3" variable_1="C3"/>
<map_variables variable_2="delta_C3_rxn_2" variable_1="delta_C3_rxn_2"/>
</connection>
<connection>
<map_components component_2="reaction3" component_1="C3"/>
<map_variables variable_2="C3" variable_1="C3"/>
<map_variables variable_2="delta_C3_rxn_3" variable_1="delta_C3_rxn_3"/>
</connection>
<connection>
<map_components component_2="reaction5" component_1="C3"/>
<map_variables variable_2="C3" variable_1="C3"/>
<map_variables variable_2="delta_C3_rxn_5" variable_1="delta_C3_rxn_5"/>
</connection>
<connection>
<map_components component_2="reaction4" component_1="O"/>
<map_variables variable_2="O" variable_1="O"/>
<map_variables variable_2="delta_O_rxn_4" variable_1="delta_O_rxn_4"/>
</connection>
<connection>
<map_components component_2="reaction5" component_1="O"/>
<map_variables variable_2="O" variable_1="O"/>
<map_variables variable_2="delta_O_rxn_5" variable_1="delta_O_rxn_5"/>
</connection>
<connection>
<map_components component_2="reaction3" component_1="I"/>
<map_variables variable_2="I" variable_1="I"/>
<map_variables variable_2="delta_I_rxn_3" variable_1="delta_I_rxn_3"/>
</connection>
<connection>
<map_components component_2="reaction4" component_1="I"/>
<map_variables variable_2="I" variable_1="I"/>
<map_variables variable_2="delta_I_rxn_4" variable_1="delta_I_rxn_4"/>
</connection>
<connection>
<map_components component_2="reaction3" component_1="reaction4"/>
<map_variables variable_2="alphai" variable_1="alphai"/>
<map_variables variable_2="betai" variable_1="betai"/>
</connection>
<connection>
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Mazhari et al's model of the molecular interactions between two long-QT
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