- Author:
- Catherine Lloyd <c.lloyd@auckland.ac.nz>
- Date:
- 2010-05-13 23:20:37+12:00
- Desc:
- Renamed model now there is only one version (the two previous versions were an error from the old repository, there should only be one model).
- Permanent Source URI:
- https://models.cellml.org/workspace/cui_kaandorp_2008/rawfile/d7e3a83dfce6e6b96408c4516a4097c6db16317e/cui_kaandorp_2008_b.cellml
<?xml version='1.0' encoding='utf-8'?>
<!-- FILE : cui_calcium_model_2008.xml
CREATED : 12th May 2008
LAST MODIFIED : 12th May 2008
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 Cui and Kaandorp's 2008 mathematical model of the calcium-calcineurin signalling network in cardiac myocytes.
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="cui_calcium_model_2008" name="cui_calcium_model_2008_version01">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>Modelling the calcium-calcineurin signalling network in cardiac myocytes</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 runs in both PCEnv and COR to recreate the published results. The units have been checked and they are consistent.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
Calcium act as a ubiquitous messenger in eukaryotic cells, playing an essential role in a diverse range of processes including cell proliferation, muscle contraction, and apoptosis. Calcium also plays a key role in controlling the hypertrophic growth of the heart through a complex calcium-calcineurin-MCIP-NFAT signalling network (see the figure below). Cardiac hypertrophy is a thickening of the muscular wall of the heart in response to stresses such as physiological and pathological stimuli. Chronic cardiac hypertrophy may progress to heart failure, thus providing a huge incentive to better understand the signalling pathways and molecular mechansims underlying the pathogenesis. Computational modelling is likely to play an important role in analysing the quantitative behaviour of such pathways, in turn providing data for the basis of potential therapeutic drug design.
</para>
<para>
In a cardiac myocyte, stress to the cell can stimulate an influx of Ca2+ which, in turn, binds to calmodulin (CaM). The Ca2+-bound CaM then binds to calcineurin (CaN) to activate it. CaN* (activated CaN) can bind to modulatory calcineurin-interacting protein (MCIP) to form Complex1 and CaN* can also act as the enzyme to catalyse the dephosphorylation of NFATP into NFAT. The reverse reaction is catalysed by GSK3β (the conversion of NFAT into NFATP), which can bind to 14-3-3 to form Complex3. In addition to these cytosolic reactions, the enzyme-catalysed, reversible conversion between NFAT and NFATP can also occur in the nuclues of the cell. Cytosolic NFAT is imported into the nucleus, where it initiates the transcription of the hypertrophic genes and the gene encoding MCIP, and nuclear NFATP is exported into the cytosol. The enzymes catalysing the interconversion of NFAT and NFATP (GSK3β and CaN*) are also shuttled between the nucleus and the cytosol.
</para>
<para>
Under alternative stresses, such as pressure overload, big mitogen-activated protein kinase 1 (BMK1) becomes activated, leading to the phosphorylation of MCIP into MCIPp, which can be further phosphorylated to MCIPpp by GSK3β. The dephosphorylation of MCIPpp into MCIPp is again catalysed by CaN*. MCIPpp will bind with 14-3-3 to form Complex2, and MCIP1 seems to facilitate or suppress cardiac CaN signalling, dependent on the nature of the stress.
</para>
<para>
In 2006, Shin <emphasis>et al.</emphasis> published a paper which modelled the dual role of MCIP in cardiac hypertrophy. In the study described here, Cui and Kaandorp have extended this model to include more recent and extensive experimental data. They used <ulink url="http://www.cellerator.org/">Cellerator</ulink>, an open source software, to automatically generate the equations, and the model was subsequently translated into CellML to facilitate future model exchange, reuse and implementation.
</para>
<informalfigure float="0" id="fig_reaction_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>model diagram</title>
</objectinfo>
<imagedata fileref="cui_calcium_2008.png"/>
</imageobject>
</mediaobject>
<caption>A schematic diagram of the Ca2+-calcineurin-MCIP-NFAT signalling networks in cardiac myocytes described by the model. Abbreviations: calmodulin (CaM); calcineurin (CaN); activated calcineurin (CaN*); nuclear factor of activated T-cells (NFAT); phosphorylated NFAT (NFATP); modulatory calcineurin-interacting protein (MCIP); phosphorylated MCIP on serine 112 (MCIPP); phosphorylated MCIP on both serine 112 and serine 108 (MCIPPP); big mitogen-activated protein kinase 1 (BMK1); glycogen synthase 3β (GSK3β); the complex formed by MCIP and calcineurin (Complex1); the complex formed by MCIPPP and 14-3-3 (Complex2); the complex formed by NFATP and 14-3-3 (Complex3); pressure overload (PO); hypertrophic stimuli (stress).</caption>
</informalfigure>
<para>
The complete original paper reference is cited below:
</para>
<para>
Simulating Complex Calcium-Calcineurin Signaling Network, Jiangjun Cui and Jaap A. Kaandorp, 2008, <ulink url="http://www.springer.com/computer/lncs?SGWID=0-164-0-0-0">
<emphasis>Lecture Notes in Computer Science</emphasis>
</ulink>, 5013, 110-119.
</para>
</sect1>
</article>
</documentation>
<units name="minute">
<unit units="second" multiplier="60.0"/>
</units>
<units name="micromolar">
<unit units="mole" prefix="nano"/>
<unit units="litre" exponent="-1"/>
</units>
<units name="flux">
<unit units="micromolar"/>
<unit units="minute" exponent="-1"/>
</units>
<units name="first_order_rate_constant">
<unit units="minute" exponent="-1"/>
</units>
<units name="second_order_rate_constant">
<unit units="micromolar" exponent="-1"/>
<unit units="minute" exponent="-1"/>
</units>
<units name="fifth_order_rate_constant">
<unit units="micromolar" exponent="-4"/>
<unit units="minute" exponent="-1"/>
</units>
<component name="environment">
<variable units="minute" public_interface="out" name="time"/>
</component>
<!-- substrates : enzymes, reactants and products -->
<component name="BMK1" cmeta:id="BMK1">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="BMK1">
<dc:title>BMK1</dc:title>
<dcterms:alternative>big mitogen-activated protein kinase 1</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="BMK1" initial_value="0.012"/>
<variable units="flux" public_interface="in" name="v10a"/>
<variable units="flux" public_interface="in" name="v10b"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>BMK1</ci>
</apply>
<apply>
<minus/>
<ci>v10b</ci>
<ci>v10a</ci>
</apply>
</apply>
</math>
</component>
<component name="MRNA" cmeta:id="MRNA">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="MRNA">
<dc:title>MRNA</dc:title>
<dcterms:alternative>MCIP mRNA</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="MRNA" initial_value="3.33E-4"/>
<variable units="flux" public_interface="in" name="v18"/>
<variable units="flux" public_interface="in" name="v19"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>MRNA</ci>
</apply>
<apply>
<minus/>
<ci>v19</ci>
<ci>v18</ci>
</apply>
</apply>
</math>
</component>
<component name="NFATc" cmeta:id="NFATc">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="NFATc">
<dc:title>NFATc</dc:title>
<dcterms:alternative>cytosolic NFAT</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="NFATc" initial_value="2E-5"/>
<variable units="flux" public_interface="in" name="v1"/>
<variable units="flux" public_interface="in" name="v14"/>
<variable units="flux" public_interface="in" name="v15"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>NFATc</ci>
</apply>
<apply>
<minus/>
<ci>v14</ci>
<apply>
<plus/>
<ci>v1</ci>
<ci>v15</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="NFATn" cmeta:id="NFATn">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="NFATn">
<dc:title>NFATn</dc:title>
<dcterms:alternative>nuclear NFAT</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="NFATn" initial_value="4.99E-4"/>
<variable units="flux" public_interface="in" name="v1"/>
<variable units="flux" public_interface="in" name="v16"/>
<variable units="flux" public_interface="in" name="v17"/>
<variable units="flux" public_interface="in" name="v18"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>NFATn</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>v1</ci>
<ci>v16</ci>
</apply>
<apply>
<plus/>
<ci>v17</ci>
<ci>v18</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="NFATpc" cmeta:id="NFATpc">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="NFATpc">
<dc:title>NFATpc</dc:title>
<dcterms:alternative>cytosolic NFATp</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="NFATpc" initial_value="4.94E-3"/>
<variable units="flux" public_interface="in" name="v2"/>
<variable units="flux" public_interface="in" name="v9"/>
<variable units="flux" public_interface="in" name="v14"/>
<variable units="flux" public_interface="in" name="v15"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>NFATpc</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>v2</ci>
<ci>v15</ci>
</apply>
<apply>
<plus/>
<ci>v9</ci>
<ci>v14</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="NFATpn" cmeta:id="NFATpn">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="NFATpn">
<dc:title>NFATpn</dc:title>
<dcterms:alternative>nuclear NFATp</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="NFATpn" initial_value="8.01E-5"/>
<variable units="flux" public_interface="in" name="v2"/>
<variable units="flux" public_interface="in" name="v16"/>
<variable units="flux" public_interface="in" name="v17"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>NFATpn</ci>
</apply>
<apply>
<minus/>
<ci>v17</ci>
<apply>
<plus/>
<ci>v2</ci>
<ci>v16</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="GSK3betac" cmeta:id="GSK3betac">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="GSK3betac">
<dc:title>GSK3betac</dc:title>
<dcterms:alternative>cytosolic glycogen synthase 3-beta</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="GSK3betac" initial_value="0.17"/>
<variable units="flux" public_interface="in" name="v3"/>
<variable units="flux" public_interface="in" name="v12a"/>
<variable units="flux" public_interface="in" name="v12b"/>
<variable units="flux" public_interface="in" name="v15a"/>
<variable units="flux" public_interface="in" name="v15b"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>GSK3betac</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>v12b</ci>
<ci>v15b</ci>
</apply>
<apply>
<plus/>
<ci>v3</ci>
<ci>v12a</ci>
<ci>v15a</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="GSK3betan" cmeta:id="GSK3betan">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="GSK3betan">
<dc:title>GSK3betan</dc:title>
<dcterms:alternative>nuclear glycogen synthase 3-beta</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="GSK3betan" initial_value="0.339"/>
<variable units="flux" public_interface="in" name="v3"/>
<variable units="flux" public_interface="in" name="v17a"/>
<variable units="flux" public_interface="in" name="v17b"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>GSK3betan</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>v3</ci>
<ci>v17b</ci>
</apply>
<ci>v17a</ci>
</apply>
</apply>
</math>
</component>
<component name="CaNc" cmeta:id="CaNc">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="CaNc">
<dc:title>CaNc</dc:title>
<dcterms:alternative>cytosolic inactive calcineurin</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="CaNc" initial_value="0.91"/>
<variable units="flux" public_interface="in" name="v6"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>CaNc</ci>
</apply>
<apply>
<minus/>
<ci>v6</ci>
</apply>
</apply>
</math>
</component>
<component name="CaNc_star" cmeta:id="CaNc_star">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="CaNc_star">
<dc:title>CaNc_star</dc:title>
<dcterms:alternative>cytosolic activated calcineurin</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="CaNc_star" initial_value="0.0275"/>
<variable units="flux" public_interface="in" name="v4"/>
<variable units="flux" public_interface="in" name="v6"/>
<variable units="flux" public_interface="in" name="v7"/>
<variable units="flux" public_interface="in" name="v11a"/>
<variable units="flux" public_interface="in" name="v11b"/>
<variable units="flux" public_interface="in" name="v13a"/>
<variable units="flux" public_interface="in" name="v13b"/>
<variable units="flux" public_interface="in" name="v14a"/>
<variable units="flux" public_interface="in" name="v14b"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>CaNc_star</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>v6</ci>
<ci>v11b</ci>
<ci>v13b</ci>
<ci>v14b</ci>
</apply>
<apply>
<plus/>
<ci>v4</ci>
<ci>v7</ci>
<ci>v11a</ci>
<ci>v13a</ci>
<ci>v14a</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="CaNn_star" cmeta:id="CaNn_star">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="CaNn_star">
<dc:title>CaNn_star</dc:title>
<dcterms:alternative>nuclear activated calcineurin</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="CaNn_star" initial_value="0.0568"/>
<variable units="flux" public_interface="in" name="v4"/>
<variable units="flux" public_interface="in" name="v16a"/>
<variable units="flux" public_interface="in" name="v16b"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>CaNn_star</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>v4</ci>
<ci>v16b</ci>
</apply>
<ci>v16a</ci>
</apply>
</apply>
</math>
</component>
<component name="CaNn" cmeta:id="CaNn">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="CaNn">
<dc:title>CaNn</dc:title>
<dcterms:alternative>nuclear inactive calcineurin</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="CaNn" initial_value="0.0057"/>
<variable units="flux" public_interface="in" name="v6"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>CaNn</ci>
</apply>
<apply>
<minus/>
<ci>v6</ci>
</apply>
</apply>
</math>
</component>
<component name="CaM" cmeta:id="CaM">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="CaM">
<dc:title>CaM</dc:title>
<dcterms:alternative>calmodulin</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="CaM" initial_value="25.2"/>
<variable units="flux" public_interface="in" name="v5"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>CaM</ci>
</apply>
<apply>
<minus/>
<ci>v5</ci>
</apply>
</apply>
</math>
</component>
<component name="CaMCa" cmeta:id="CaMCa">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="CaMCa">
<dc:title>CaMCa</dc:title>
<dcterms:alternative>calcium-calmodulin complex</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="CaMCa" initial_value="7.88E-7"/>
<variable units="flux" public_interface="in" name="v5"/>
<variable units="flux" public_interface="in" name="v6"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>CaMCa</ci>
</apply>
<apply>
<minus/>
<ci>v5</ci>
<ci>v6</ci>
</apply>
</apply>
</math>
</component>
<component name="MCIP" cmeta:id="MCIP">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="MCIP">
<dc:title>MCIP</dc:title>
<dcterms:alternative>modulatory calcineurin-interacting protein</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="MCIP" initial_value="2.15E-4"/>
<variable units="flux" public_interface="in" name="v7"/>
<variable units="flux" public_interface="in" name="v10"/>
<variable units="flux" public_interface="in" name="v11"/>
<variable units="flux" public_interface="in" name="v19"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>MCIP</ci>
</apply>
<apply>
<minus/>
<ci>v11</ci>
<apply>
<plus/>
<ci>v7</ci>
<ci>v10</ci>
<ci>v19</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="MCIPp" cmeta:id="MCIPp">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="MCIPp">
<dc:title>MCIPp</dc:title>
<dcterms:alternative>phosphorylated MCIP on serine 112</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="MCIPp" initial_value="7.76E-3"/>
<variable units="flux" public_interface="in" name="v10"/>
<variable units="flux" public_interface="in" name="v11"/>
<variable units="flux" public_interface="in" name="v12"/>
<variable units="flux" public_interface="in" name="v13"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>MCIPp</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>v10</ci>
<ci>v13</ci>
</apply>
<apply>
<plus/>
<ci>v11</ci>
<ci>v12</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="MCIPpp" cmeta:id="MCIPpp">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="MCIPpp">
<dc:title>MCIPpp</dc:title>
<dcterms:alternative>phosphorylated MCIP on both serine 112 and serine 108</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="MCIPpp" initial_value="0.0798"/>
<variable units="flux" public_interface="in" name="v8"/>
<variable units="flux" public_interface="in" name="v12"/>
<variable units="flux" public_interface="in" name="v13"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>MCIPpp</ci>
</apply>
<apply>
<minus/>
<ci>v12</ci>
<apply>
<plus/>
<ci>v8</ci>
<ci>v13</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="Comp1" cmeta:id="Comp1">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="Comp1">
<dc:title>Comp1</dc:title>
<dcterms:alternative>complex formed by MCIP and calcineurin</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="Comp1" initial_value="5.21E-3"/>
<variable units="flux" public_interface="in" name="v7"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Comp1</ci>
</apply>
<ci>v7</ci>
</apply>
</math>
</component>
<component name="Comp2" cmeta:id="Comp2">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="Comp2">
<dc:title>Comp2</dc:title>
<dcterms:alternative>complex formed by MCIPPP and 14-3-3</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="Comp2" initial_value="0.283"/>
<variable units="flux" public_interface="in" name="v8"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Comp2</ci>
</apply>
<ci>v8</ci>
</apply>
</math>
</component>
<component name="Comp3" cmeta:id="Comp3">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="Comp3">
<dc:title>Comp3</dc:title>
<dcterms:alternative>complex formed by NFATP and 14-3-3</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="Comp3" initial_value="0.014"/>
<variable units="flux" public_interface="in" name="v9"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Comp3</ci>
</apply>
<ci>v9</ci>
</apply>
</math>
</component>
<component name="P1433" cmeta:id="P1433">
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<rdf:Description rdf:about="P1433">
<dc:title>P1433</dc:title>
<dcterms:alternative>14-3-3 protein</dcterms:alternative>
</rdf:Description>
</rdf:RDF>
<variable units="micromolar" public_interface="out" name="P1433" initial_value="0.708"/>
<variable units="flux" public_interface="in" name="v8"/>
<variable units="flux" public_interface="in" name="v9"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>P1433</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<ci>v8</ci>
<ci>v9</ci>
</apply>
</apply>
</apply>
</math>
</component>
<!-- reactants-enzyme complexes -->
<component name="MCIP_BMK1">
<variable units="micromolar" public_interface="out" name="MCIP_BMK1" initial_value="2.14E-5"/>
<variable units="flux" public_interface="in" name="v10a"/>
<variable units="flux" public_interface="in" name="v10b"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>MCIP_BMK1</ci>
</apply>
<apply>
<minus/>
<ci>v10a</ci>
<ci>v10b</ci>
</apply>
</apply>
</math>
</component>
<component name="MCIPp_CaNc_star">
<variable units="micromolar" public_interface="out" name="MCIPp_CaNc_star" initial_value="1.07E-4"/>
<variable units="flux" public_interface="in" name="v11a"/>
<variable units="flux" public_interface="in" name="v11b"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>MCIPp_CaNc_star</ci>
</apply>
<apply>
<minus/>
<ci>v11a</ci>
<ci>v11b</ci>
</apply>
</apply>
</math>
</component>
<component name="MCIPp_GSK3betac">
<variable units="micromolar" public_interface="out" name="MCIPp_GSK3betac" initial_value="1.1E-3"/>
<variable units="flux" public_interface="in" name="v12a"/>
<variable units="flux" public_interface="in" name="v12b"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>MCIPp_GSK3betac</ci>
</apply>
<apply>
<minus/>
<ci>v12a</ci>
<ci>v12b</ci>
</apply>
</apply>
</math>
</component>
<component name="MCIPpp_CaNc_star">
<variable units="micromolar" public_interface="out" name="MCIPpp_CaNc_star" initial_value="1.1E-3"/>
<variable units="flux" public_interface="in" name="v13a"/>
<variable units="flux" public_interface="in" name="v13b"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>MCIPpp_CaNc_star</ci>
</apply>
<apply>
<minus/>
<ci>v13a</ci>
<ci>v13b</ci>
</apply>
</apply>
</math>
</component>
<component name="NFATpc_CaNc_star">
<variable units="micromolar" public_interface="out" name="NFATpc_CaNc_star" initial_value="8.15E-5"/>
<variable units="flux" public_interface="in" name="v14a"/>
<variable units="flux" public_interface="in" name="v14b"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>NFATpc_CaNc_star</ci>
</apply>
<apply>
<minus/>
<ci>v14a</ci>
<ci>v14b</ci>
</apply>
</apply>
</math>
</component>
<component name="NFATc_GSK3betac">
<variable units="micromolar" public_interface="out" name="NFATc_GSK3betac" initial_value="1.36E-6"/>
<variable units="flux" public_interface="in" name="v15a"/>
<variable units="flux" public_interface="in" name="v15b"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>NFATc_GSK3betac</ci>
</apply>
<apply>
<minus/>
<ci>v15a</ci>
<ci>v15b</ci>
</apply>
</apply>
</math>
</component>
<component name="NFATpn_CaNn_star">
<variable units="micromolar" public_interface="out" name="NFATpn_CaNn_star" initial_value="2.27E-6"/>
<variable units="flux" public_interface="in" name="v16a"/>
<variable units="flux" public_interface="in" name="v16b"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>NFATpn_CaNn_star</ci>
</apply>
<apply>
<minus/>
<ci>v16a</ci>
<ci>v16b</ci>
</apply>
</apply>
</math>
</component>
<component name="NFATn_GSK3betan">
<variable units="micromolar" public_interface="out" name="NFATn_GSK3betan" initial_value="8.46E-5"/>
<variable units="flux" public_interface="in" name="v17a"/>
<variable units="flux" public_interface="in" name="v17b"/>
<variable units="minute" public_interface="in" name="time"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>NFATn_GSK3betan</ci>
</apply>
<apply>
<minus/>
<ci>v17a</ci>
<ci>v17b</ci>
</apply>
</apply>
</math>
</component>
<!-- Simple Irreversible Reactions -->
<component name="v1">
<variable units="flux" public_interface="out" name="v1"/>
<variable units="micromolar" public_interface="in" name="NFATc"/>
<variable units="first_order_rate_constant" public_interface="in" name="k29"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v1 </ci>
<apply>
<times/>
<ci> k29 </ci>
<ci> NFATc </ci>
</apply>
</apply>
</math>
</component>
<component name="v2">
<variable units="flux" public_interface="out" name="v2"/>
<variable units="micromolar" public_interface="in" name="NFATpn"/>
<variable units="first_order_rate_constant" public_interface="in" name="k30"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v2 </ci>
<apply>
<times/>
<ci> k30 </ci>
<ci> NFATpn </ci>
</apply>
</apply>
</math>
</component>
<!-- Simple Reversible Reactions -->
<component name="v3">
<variable units="flux" public_interface="out" name="v3"/>
<variable units="micromolar" public_interface="in" name="GSK3betac"/>
<variable units="micromolar" public_interface="in" name="GSK3betan"/>
<variable units="first_order_rate_constant" public_interface="in" name="k31"/>
<variable units="first_order_rate_constant" public_interface="in" name="k32"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v3 </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k31 </ci>
<ci> GSK3betac </ci>
</apply>
<apply>
<times/>
<ci> k32 </ci>
<ci> GSK3betan </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v4">
<variable units="flux" public_interface="out" name="v4"/>
<variable units="micromolar" public_interface="in" name="CaNc_star"/>
<variable units="micromolar" public_interface="in" name="CaNn_star"/>
<variable units="first_order_rate_constant" public_interface="in" name="k33"/>
<variable units="first_order_rate_constant" public_interface="in" name="k34"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v4 </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k33 </ci>
<ci> CaNc_star </ci>
</apply>
<apply>
<times/>
<ci> k34 </ci>
<ci> CaNn_star </ci>
</apply>
</apply>
</apply>
</math>
</component>
<!-- Reversible Binding Reactions -->
<component name="v5">
<variable units="flux" public_interface="out" name="v5"/>
<variable units="micromolar" public_interface="in" name="CaM"/>
<variable units="micromolar" public_interface="in" name="Ca"/>
<variable units="micromolar" public_interface="in" name="CaMCa"/>
<variable units="fifth_order_rate_constant" public_interface="in" name="k1"/>
<variable units="first_order_rate_constant" public_interface="in" name="k2"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v5 </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k1 </ci>
<ci> CaM </ci>
<apply>
<power/>
<ci> Ca </ci>
<cn cellml:units="dimensionless"> 4 </cn>
</apply>
</apply>
<apply>
<times/>
<ci> k2 </ci>
<ci> CaMCa </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v6">
<variable units="flux" public_interface="out" name="v6"/>
<variable units="micromolar" public_interface="in" name="CaNc"/>
<variable units="micromolar" public_interface="in" name="CaNc_star"/>
<variable units="micromolar" public_interface="in" name="CaMCa"/>
<variable units="second_order_rate_constant" public_interface="in" name="k3"/>
<variable units="first_order_rate_constant" public_interface="in" name="k4"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v6 </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k3 </ci>
<ci> CaMCa </ci>
<ci> CaNc </ci>
</apply>
<apply>
<times/>
<ci> k4 </ci>
<ci> CaNc_star </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v7">
<variable units="flux" public_interface="out" name="v7"/>
<variable units="micromolar" public_interface="in" name="MCIP"/>
<variable units="micromolar" public_interface="in" name="CaNc_star"/>
<variable units="micromolar" public_interface="in" name="Comp1"/>
<variable units="second_order_rate_constant" public_interface="in" name="k5"/>
<variable units="first_order_rate_constant" public_interface="in" name="k6"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v7 </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k5 </ci>
<ci> CaNc_star </ci>
<ci> MCIP </ci>
</apply>
<apply>
<times/>
<ci> k6 </ci>
<ci> Comp1 </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v8">
<variable units="flux" public_interface="out" name="v8"/>
<variable units="micromolar" public_interface="in" name="MCIPpp"/>
<variable units="micromolar" public_interface="in" name="P1433"/>
<variable units="micromolar" public_interface="in" name="Comp2"/>
<variable units="second_order_rate_constant" public_interface="in" name="k19"/>
<variable units="first_order_rate_constant" public_interface="in" name="k20"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v8 </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k19 </ci>
<ci> P1433 </ci>
<ci> MCIPpp </ci>
</apply>
<apply>
<times/>
<ci> k20 </ci>
<ci> Comp2 </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v9">
<variable units="flux" public_interface="out" name="v9"/>
<variable units="micromolar" public_interface="in" name="NFATpc"/>
<variable units="micromolar" public_interface="in" name="P1433"/>
<variable units="micromolar" public_interface="in" name="Comp3"/>
<variable units="second_order_rate_constant" public_interface="in" name="k27"/>
<variable units="first_order_rate_constant" public_interface="in" name="k28"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v9 </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k27 </ci>
<ci> NFATpc </ci>
<ci> P1433 </ci>
</apply>
<apply>
<times/>
<ci> k28 </ci>
<ci> Comp3 </ci>
</apply>
</apply>
</apply>
</math>
</component>
<!-- Catalytic Binding Reactions -->
<component name="v10">
<variable units="flux" public_interface="out" name="v10"/>
<variable units="flux" public_interface="out" name="v10a"/>
<variable units="flux" public_interface="out" name="v10b"/>
<variable units="micromolar" public_interface="in" name="BMK1"/>
<variable units="micromolar" public_interface="in" name="MCIP_BMK1"/>
<variable units="micromolar" public_interface="in" name="MCIP"/>
<variable units="second_order_rate_constant" public_interface="in" name="k7"/>
<variable units="first_order_rate_constant" public_interface="in" name="k8"/>
<variable units="first_order_rate_constant" public_interface="in" name="k9"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v10a </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k7 </ci>
<ci> MCIP </ci>
<ci> BMK1 </ci>
</apply>
<apply>
<times/>
<ci> k8 </ci>
<ci> MCIP_BMK1 </ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci> v10b </ci>
<apply>
<times/>
<ci> k9 </ci>
<ci> MCIP_BMK1 </ci>
</apply>
</apply>
<apply>
<eq/>
<ci> v10 </ci>
<apply>
<plus/>
<ci> v10a </ci>
<ci> v10b </ci>
</apply>
</apply>
</math>
</component>
<component name="v11">
<variable units="flux" public_interface="out" name="v11"/>
<variable units="flux" public_interface="out" name="v11a"/>
<variable units="flux" public_interface="out" name="v11b"/>
<variable units="micromolar" public_interface="in" name="MCIPp_CaNc_star"/>
<variable units="micromolar" public_interface="in" name="CaNc_star"/>
<variable units="micromolar" public_interface="in" name="MCIPp"/>
<variable units="second_order_rate_constant" public_interface="in" name="k10"/>
<variable units="first_order_rate_constant" public_interface="in" name="k11"/>
<variable units="first_order_rate_constant" public_interface="in" name="k12"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v11a </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k10 </ci>
<ci> MCIPp </ci>
<ci> CaNc_star </ci>
</apply>
<apply>
<times/>
<ci> k11 </ci>
<ci> MCIPp_CaNc_star </ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci> v11b </ci>
<apply>
<times/>
<ci> k12 </ci>
<ci> MCIPp_CaNc_star </ci>
</apply>
</apply>
<apply>
<eq/>
<ci> v11 </ci>
<apply>
<plus/>
<ci> v11a </ci>
<ci> v11b </ci>
</apply>
</apply>
</math>
</component>
<component name="v12">
<variable units="flux" public_interface="out" name="v12"/>
<variable units="flux" public_interface="out" name="v12a"/>
<variable units="flux" public_interface="out" name="v12b"/>
<variable units="micromolar" public_interface="in" name="MCIPp_GSK3betac"/>
<variable units="micromolar" public_interface="in" name="GSK3betac"/>
<variable units="micromolar" public_interface="in" name="MCIPp"/>
<variable units="second_order_rate_constant" public_interface="in" name="k13"/>
<variable units="first_order_rate_constant" public_interface="in" name="k14"/>
<variable units="first_order_rate_constant" public_interface="in" name="k15"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v12a </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k13 </ci>
<ci> MCIPp </ci>
<ci> GSK3betac </ci>
</apply>
<apply>
<times/>
<ci> k14 </ci>
<ci> MCIPp_GSK3betac </ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci> v12b </ci>
<apply>
<times/>
<ci> k15 </ci>
<ci> MCIPp_GSK3betac </ci>
</apply>
</apply>
<apply>
<eq/>
<ci> v12 </ci>
<apply>
<plus/>
<ci> v12a </ci>
<ci> v12b </ci>
</apply>
</apply>
</math>
</component>
<component name="v13">
<variable units="flux" public_interface="out" name="v13"/>
<variable units="flux" public_interface="out" name="v13a"/>
<variable units="flux" public_interface="out" name="v13b"/>
<variable units="micromolar" public_interface="in" name="MCIPpp_CaNc_star"/>
<variable units="micromolar" public_interface="in" name="CaNc_star"/>
<variable units="micromolar" public_interface="in" name="MCIPpp"/>
<variable units="second_order_rate_constant" public_interface="in" name="k16"/>
<variable units="first_order_rate_constant" public_interface="in" name="k17"/>
<variable units="first_order_rate_constant" public_interface="in" name="k18"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v13a </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k16 </ci>
<ci> MCIPpp </ci>
<ci> CaNc_star </ci>
</apply>
<apply>
<times/>
<ci> k17 </ci>
<ci> MCIPpp_CaNc_star </ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci> v13b </ci>
<apply>
<times/>
<ci> k18 </ci>
<ci> MCIPpp_CaNc_star </ci>
</apply>
</apply>
<apply>
<eq/>
<ci> v13 </ci>
<apply>
<plus/>
<ci> v13a </ci>
<ci> v13b </ci>
</apply>
</apply>
</math>
</component>
<component name="v14">
<variable units="flux" public_interface="out" name="v14"/>
<variable units="flux" public_interface="out" name="v14a"/>
<variable units="flux" public_interface="out" name="v14b"/>
<variable units="micromolar" public_interface="in" name="NFATpc_CaNc_star"/>
<variable units="micromolar" public_interface="in" name="CaNc_star"/>
<variable units="micromolar" public_interface="in" name="NFATpc"/>
<variable units="second_order_rate_constant" public_interface="in" name="k21"/>
<variable units="first_order_rate_constant" public_interface="in" name="k22"/>
<variable units="first_order_rate_constant" public_interface="in" name="k23"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v14a </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k21 </ci>
<ci> NFATpc </ci>
<ci> CaNc_star </ci>
</apply>
<apply>
<times/>
<ci> k22 </ci>
<ci> NFATpc_CaNc_star </ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci> v14b </ci>
<apply>
<times/>
<ci> k23 </ci>
<ci> NFATpc_CaNc_star </ci>
</apply>
</apply>
<apply>
<eq/>
<ci> v14 </ci>
<apply>
<plus/>
<ci> v14a </ci>
<ci> v14b </ci>
</apply>
</apply>
</math>
</component>
<component name="v15">
<variable units="flux" public_interface="out" name="v15"/>
<variable units="flux" public_interface="out" name="v15a"/>
<variable units="flux" public_interface="out" name="v15b"/>
<variable units="micromolar" public_interface="in" name="NFATc_GSK3betac"/>
<variable units="micromolar" public_interface="in" name="GSK3betac"/>
<variable units="micromolar" public_interface="in" name="NFATc"/>
<variable units="second_order_rate_constant" public_interface="in" name="k24"/>
<variable units="first_order_rate_constant" public_interface="in" name="k25"/>
<variable units="first_order_rate_constant" public_interface="in" name="k26"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v15a </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k24 </ci>
<ci> NFATc </ci>
<ci> GSK3betac </ci>
</apply>
<apply>
<times/>
<ci> k25 </ci>
<ci> NFATc_GSK3betac </ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci> v15b </ci>
<apply>
<times/>
<ci> k26 </ci>
<ci> NFATc_GSK3betac </ci>
</apply>
</apply>
<apply>
<eq/>
<ci> v15 </ci>
<apply>
<plus/>
<ci> v15a </ci>
<ci> v15b </ci>
</apply>
</apply>
</math>
</component>
<component name="v16">
<variable units="flux" public_interface="out" name="v16"/>
<variable units="flux" public_interface="out" name="v16a"/>
<variable units="flux" public_interface="out" name="v16b"/>
<variable units="micromolar" public_interface="in" name="NFATpn_CaNn_star"/>
<variable units="micromolar" public_interface="in" name="CaNn_star"/>
<variable units="micromolar" public_interface="in" name="NFATpn"/>
<variable units="second_order_rate_constant" public_interface="in" name="k35"/>
<variable units="first_order_rate_constant" public_interface="in" name="k36"/>
<variable units="first_order_rate_constant" public_interface="in" name="k37"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v16a </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k35 </ci>
<ci> NFATpn </ci>
<ci> CaNn_star </ci>
</apply>
<apply>
<times/>
<ci> k36 </ci>
<ci> NFATpn_CaNn_star </ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci> v16b </ci>
<apply>
<times/>
<ci> k37 </ci>
<ci> NFATpn_CaNn_star </ci>
</apply>
</apply>
<apply>
<eq/>
<ci> v16 </ci>
<apply>
<plus/>
<ci> v16a </ci>
<ci> v16b </ci>
</apply>
</apply>
</math>
</component>
<component name="v17">
<variable units="flux" public_interface="out" name="v17"/>
<variable units="flux" public_interface="out" name="v17a"/>
<variable units="flux" public_interface="out" name="v17b"/>
<variable units="micromolar" public_interface="in" name="NFATn_GSK3betan"/>
<variable units="micromolar" public_interface="in" name="GSK3betan"/>
<variable units="micromolar" public_interface="in" name="NFATn"/>
<variable units="second_order_rate_constant" public_interface="in" name="k38"/>
<variable units="first_order_rate_constant" public_interface="in" name="k39"/>
<variable units="first_order_rate_constant" public_interface="in" name="k40"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v17a </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k38 </ci>
<ci> NFATn </ci>
<ci> GSK3betan </ci>
</apply>
<apply>
<times/>
<ci> k39 </ci>
<ci> NFATn_GSK3betan </ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci> v17b </ci>
<apply>
<times/>
<ci> k40 </ci>
<ci> NFATn_GSK3betan </ci>
</apply>
</apply>
<apply>
<eq/>
<ci> v17 </ci>
<apply>
<plus/>
<ci> v17a </ci>
<ci> v17b </ci>
</apply>
</apply>
</math>
</component>
<!-- transcription control process of MCIP by NFAT -->
<component name="v18">
<variable units="flux" public_interface="out" name="v18"/>
<variable units="micromolar" public_interface="in" name="NFATn"/>
<variable units="micromolar" public_interface="in" name="MRNA"/>
<variable units="first_order_rate_constant" public_interface="in" name="k41"/>
<variable units="first_order_rate_constant" public_interface="in" name="k42"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v18 </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k41 </ci>
<ci> NFATn </ci>
</apply>
<apply>
<times/>
<ci> k42 </ci>
<ci> MRNA </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="v19">
<variable units="flux" public_interface="out" name="v19"/>
<variable units="minute" public_interface="in" name="t_half"/>
<variable units="micromolar" public_interface="in" name="MRNA"/>
<variable units="micromolar" public_interface="in" name="MCIP"/>
<variable units="first_order_rate_constant" public_interface="in" name="k43"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci> v19 </ci>
<apply>
<minus/>
<apply>
<times/>
<ci> k43 </ci>
<ci> MRNA </ci>
</apply>
<apply>
<times/>
<apply>
<divide/>
<apply>
<ln/>
<cn cellml:units="dimensionless"> 2.0 </cn>
</apply>
<ci> t_half </ci>
</apply>
<ci> MCIP </ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="model_parameters">
<variable units="fifth_order_rate_constant" public_interface="out" name="k1" initial_value="5"/>
<variable units="first_order_rate_constant" public_interface="out" name="k2" initial_value="100"/>
<variable units="second_order_rate_constant" public_interface="out" name="k3" initial_value="2760"/>
<variable units="first_order_rate_constant" public_interface="out" name="k4" initial_value="0.072"/>
<variable units="second_order_rate_constant" public_interface="out" name="k5" initial_value="50"/>
<variable units="first_order_rate_constant" public_interface="out" name="k6" initial_value="0.0567"/>
<variable units="second_order_rate_constant" public_interface="out" name="k7" initial_value="5"/>
<variable units="first_order_rate_constant" public_interface="out" name="k8" initial_value="0.1"/>
<variable units="first_order_rate_constant" public_interface="out" name="k9" initial_value="0.5"/>
<variable units="second_order_rate_constant" public_interface="out" name="k10" initial_value="0.1"/>
<variable units="first_order_rate_constant" public_interface="out" name="k11" initial_value="0.1"/>
<variable units="first_order_rate_constant" public_interface="out" name="k12" initial_value="0.1"/>
<variable units="second_order_rate_constant" public_interface="out" name="k13" initial_value="0.5"/>
<variable units="first_order_rate_constant" public_interface="out" name="k14" initial_value="0.5"/>
<variable units="first_order_rate_constant" public_interface="out" name="k15" initial_value="0.1"/>
<variable units="second_order_rate_constant" public_interface="out" name="k16" initial_value="0.1"/>
<variable units="first_order_rate_constant" public_interface="out" name="k17" initial_value="0.1"/>
<variable units="first_order_rate_constant" public_interface="out" name="k18" initial_value="0.1"/>
<variable units="second_order_rate_constant" public_interface="out" name="k19" initial_value="0.5"/>
<variable units="first_order_rate_constant" public_interface="out" name="k20" initial_value="0.1"/>
<variable units="second_order_rate_constant" public_interface="out" name="k21" initial_value="0.15"/>
<variable units="first_order_rate_constant" public_interface="out" name="k22" initial_value="0.15"/>
<variable units="first_order_rate_constant" public_interface="out" name="k23" initial_value="0.15"/>
<variable units="second_order_rate_constant" public_interface="out" name="k24" initial_value="0.1"/>
<variable units="first_order_rate_constant" public_interface="out" name="k25" initial_value="0.15"/>
<variable units="first_order_rate_constant" public_interface="out" name="k26" initial_value="0.1"/>
<variable units="second_order_rate_constant" public_interface="out" name="k27" initial_value="0.4"/>
<variable units="first_order_rate_constant" public_interface="out" name="k28" initial_value="0.1"/>
<variable units="first_order_rate_constant" public_interface="out" name="k29" initial_value="0.4"/>
<variable units="first_order_rate_constant" public_interface="out" name="k30" initial_value="0.1"/>
<variable units="first_order_rate_constant" public_interface="out" name="k31" initial_value="0.1"/>
<variable units="first_order_rate_constant" public_interface="out" name="k32" initial_value="0.05"/>
<variable units="first_order_rate_constant" public_interface="out" name="k33" initial_value="0.114"/>
<variable units="first_order_rate_constant" public_interface="out" name="k34" initial_value="0.0552"/>
<variable units="second_order_rate_constant" public_interface="out" name="k35" initial_value="0.15"/>
<variable units="first_order_rate_constant" public_interface="out" name="k36" initial_value="0.1"/>
<variable units="first_order_rate_constant" public_interface="out" name="k37" initial_value="0.2"/>
<variable units="second_order_rate_constant" public_interface="out" name="k38" initial_value="0.1"/>
<variable units="first_order_rate_constant" public_interface="out" name="k39" initial_value="0.1"/>
<variable units="first_order_rate_constant" public_interface="out" name="k40" initial_value="0.1"/>
<variable units="first_order_rate_constant" public_interface="out" name="k41" initial_value="0.02"/>
<variable units="first_order_rate_constant" public_interface="out" name="k42" initial_value="0.03"/>
<variable units="first_order_rate_constant" public_interface="out" name="k43" initial_value="0.03"/>
<variable units="minute" public_interface="out" name="t_half" initial_value="15"/>
<variable units="micromolar" public_interface="out" name="Ca" initial_value="0.2"/>
</component>
<connection>
<map_components component_2="environment" component_1="BMK1"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="MRNA"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="NFATc"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="NFATn"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="NFATpc"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="NFATpn"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="GSK3betac"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="GSK3betan"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="CaNc"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="CaNn"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="CaNc_star"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="CaNn_star"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="CaM"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="CaMCa"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="MCIP"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="MCIPp"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="MCIPpp"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="Comp1"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="Comp2"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="Comp3"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="P1433"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="MCIP_BMK1"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="MCIPp_CaNc_star"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="MCIPp_GSK3betac"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="MCIPpp_CaNc_star"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="NFATpc_CaNc_star"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="NFATc_GSK3betac"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="NFATpn_CaNn_star"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="environment" component_1="NFATn_GSK3betan"/>
<map_variables variable_2="time" variable_1="time"/>
</connection>
<connection>
<map_components component_2="BMK1" component_1="v10"/>
<map_variables variable_2="v10a" variable_1="v10a"/>
<map_variables variable_2="v10b" variable_1="v10b"/>
<map_variables variable_2="BMK1" variable_1="BMK1"/>
</connection>
<connection>
<map_components component_2="MRNA" component_1="v18"/>
<map_variables variable_2="v18" variable_1="v18"/>
<map_variables variable_2="MRNA" variable_1="MRNA"/>
</connection>
<connection>
<map_components component_2="MRNA" component_1="v19"/>
<map_variables variable_2="v19" variable_1="v19"/>
<map_variables variable_2="MRNA" variable_1="MRNA"/>
</connection>
<connection>
<map_components component_2="NFATc" component_1="v1"/>
<map_variables variable_2="v1" variable_1="v1"/>
<map_variables variable_2="NFATc" variable_1="NFATc"/>
</connection>
<connection>
<map_components component_2="NFATc" component_1="v14"/>
<map_variables variable_2="v14" variable_1="v14"/>
</connection>
<connection>
<map_components component_2="NFATc" component_1="v15"/>
<map_variables variable_2="v15" variable_1="v15"/>
<map_variables variable_2="NFATc" variable_1="NFATc"/>
</connection>
<connection>
<map_components component_2="NFATn" component_1="v1"/>
<map_variables variable_2="v1" variable_1="v1"/>
</connection>
<connection>
<map_components component_2="NFATn" component_1="v16"/>
<map_variables variable_2="v16" variable_1="v16"/>
</connection>
<connection>
<map_components component_2="NFATn" component_1="v17"/>
<map_variables variable_2="v17" variable_1="v17"/>
<map_variables variable_2="NFATn" variable_1="NFATn"/>
</connection>
<connection>
<map_components component_2="NFATn" component_1="v18"/>
<map_variables variable_2="v18" variable_1="v18"/>
<map_variables variable_2="NFATn" variable_1="NFATn"/>
</connection>
<connection>
<map_components component_2="NFATpc" component_1="v2"/>
<map_variables variable_2="v2" variable_1="v2"/>
</connection>
<connection>
<map_components component_2="NFATpc" component_1="v9"/>
<map_variables variable_2="v9" variable_1="v9"/>
<map_variables variable_2="NFATpc" variable_1="NFATpc"/>
</connection>
<connection>
<map_components component_2="NFATpc" component_1="v14"/>
<map_variables variable_2="v14" variable_1="v14"/>
<map_variables variable_2="NFATpc" variable_1="NFATpc"/>
</connection>
<connection>
<map_components component_2="NFATpc" component_1="v15"/>
<map_variables variable_2="v15" variable_1="v15"/>
</connection>
<connection>
<map_components component_2="NFATpn" component_1="v2"/>
<map_variables variable_2="v2" variable_1="v2"/>
<map_variables variable_2="NFATpn" variable_1="NFATpn"/>
</connection>
<connection>
<map_components component_2="NFATpn" component_1="v16"/>
<map_variables variable_2="v16" variable_1="v16"/>
<map_variables variable_2="NFATpn" variable_1="NFATpn"/>
</connection>
<connection>
<map_components component_2="NFATpn" component_1="v17"/>
<map_variables variable_2="v17" variable_1="v17"/>
</connection>
<connection>
<map_components component_2="GSK3betac" component_1="v3"/>
<map_variables variable_2="v3" variable_1="v3"/>
<map_variables variable_2="GSK3betac" variable_1="GSK3betac"/>
</connection>
<connection>
<map_components component_2="GSK3betac" component_1="v12"/>
<map_variables variable_2="v12a" variable_1="v12a"/>
<map_variables variable_2="v12b" variable_1="v12b"/>
<map_variables variable_2="GSK3betac" variable_1="GSK3betac"/>
</connection>
<connection>
<map_components component_2="GSK3betac" component_1="v15"/>
<map_variables variable_2="v15a" variable_1="v15a"/>
<map_variables variable_2="v15b" variable_1="v15b"/>
<map_variables variable_2="GSK3betac" variable_1="GSK3betac"/>
</connection>
<connection>
<map_components component_2="GSK3betan" component_1="v3"/>
<map_variables variable_2="v3" variable_1="v3"/>
<map_variables variable_2="GSK3betan" variable_1="GSK3betan"/>
</connection>
<connection>
<map_components component_2="GSK3betan" component_1="v17"/>
<map_variables variable_2="v17a" variable_1="v17a"/>
<map_variables variable_2="v17b" variable_1="v17b"/>
<map_variables variable_2="GSK3betan" variable_1="GSK3betan"/>
</connection>
<connection>
<map_components component_2="CaNc" component_1="v6"/>
<map_variables variable_2="v6" variable_1="v6"/>
<map_variables variable_2="CaNc" variable_1="CaNc"/>
</connection>
<connection>
<map_components component_2="CaNc_star" component_1="v4"/>
<map_variables variable_2="v4" variable_1="v4"/>
<map_variables variable_2="CaNc_star" variable_1="CaNc_star"/>
</connection>
<connection>
<map_components component_2="CaNc_star" component_1="v6"/>
<map_variables variable_2="v6" variable_1="v6"/>
<map_variables variable_2="CaNc_star" variable_1="CaNc_star"/>
</connection>
<connection>
<map_components component_2="CaNc_star" component_1="v7"/>
<map_variables variable_2="v7" variable_1="v7"/>
<map_variables variable_2="CaNc_star" variable_1="CaNc_star"/>
</connection>
<connection>
<map_components component_2="CaNc_star" component_1="v11"/>
<map_variables variable_2="v11a" variable_1="v11a"/>
<map_variables variable_2="v11b" variable_1="v11b"/>
<map_variables variable_2="CaNc_star" variable_1="CaNc_star"/>
</connection>
<connection>
<map_components component_2="CaNc_star" component_1="v13"/>
<map_variables variable_2="v13a" variable_1="v13a"/>
<map_variables variable_2="v13b" variable_1="v13b"/>
<map_variables variable_2="CaNc_star" variable_1="CaNc_star"/>
</connection>
<connection>
<map_components component_2="CaNc_star" component_1="v14"/>
<map_variables variable_2="v14a" variable_1="v14a"/>
<map_variables variable_2="v14b" variable_1="v14b"/>
<map_variables variable_2="CaNc_star" variable_1="CaNc_star"/>
</connection>
<connection>
<map_components component_2="CaNn_star" component_1="v4"/>
<map_variables variable_2="v4" variable_1="v4"/>
<map_variables variable_2="CaNn_star" variable_1="CaNn_star"/>
</connection>
<connection>
<map_components component_2="CaNn_star" component_1="v16"/>
<map_variables variable_2="v16a" variable_1="v16a"/>
<map_variables variable_2="v16b" variable_1="v16b"/>
<map_variables variable_2="CaNn_star" variable_1="CaNn_star"/>
</connection>
<connection>
<map_components component_2="CaNn" component_1="v6"/>
<map_variables variable_2="v6" variable_1="v6"/>
</connection>
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