- Author:
- Hanne <Hanne@hanne-nielsens-macbook.local>
- Date:
- 2009-10-27 12:40:55+13:00
- Desc:
- Added images in ai and svg format
- Permanent Source URI:
- http://models.cellml.org/workspace/iancu_2007/rawfile/9d92e9ff75099d6161afd11d3d25f22ae6c908d2/iancu_jones_harvey_2007.cellml
<?xml version="1.0" encoding="utf-8"?>
<!--
This CellML file was generated on 13/10/2009 at 9:44:46 at a.m. using:
COR (0.9.31.1319)
Copyright 2002-2009 Dr Alan Garny
http://cor.physiol.ox.ac.uk/ - cor@physiol.ox.ac.uk
CellML 1.0 was used to generate this model
http://www.cellml.org/
-->
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<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>Compartmentation of cAMP signaling in cardiac myocytes: a computational study
</title>
<author>
<firstname>Geoffrey</firstname>
<surname>Nunns</surname>
<affiliation>
<shortaffil>Bioengineering Institute, University of Auckland</shortaffil>
</affiliation>
</author>
</articleinfo>
<section id="sec_status">
<title>Model Status</title>
<para>
This CellML model does not run in COR due to the presence of DAEs, but runs in PCEnv and OpenCell to reproduce the published results. The CellML model has been based on the published paper and later corrections.
</para>
</section>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
ABSTRACT: Receptor-mediated changes in cAMP production play an essential role in sympathetic and parasympathetic regulation of the electrical, mechanical, and metabolic activity of cardiac myocytes. However, responses to receptor activation cannot be easily ascribed to a uniform increase or decrease in cAMP activity throughout the entire cell. In this study, we used a computational approach to test the hypothesis that in cardiac ventricular myocytes the effects of beta(1)-adrenergic receptor (beta(1)AR) and M(2) muscarinic receptor (M(2)R) activation involve compartmentation of cAMP. A model consisting of two submembrane (caveolar and extracaveolar) microdomains and one bulk cytosolic domain was created using published information on the location of beta(1)ARs and M(2)Rs, as well as the location of stimulatory (G(s)) and inhibitory (G(i)) G-proteins, adenylyl cyclase isoforms inhibited (AC5/6) and stimulated (AC4/7) by G(i), and multiple phosphodiesterase isoforms (PDE2, PDE3, and PDE4). Results obtained with the model indicate that: 1), bulk basal cAMP can be high ( approximately 1 microM) and only modestly stimulated by beta(1)AR activation ( approximately 2 microM), but caveolar cAMP varies in a range more appropriate for regulation of protein kinase A ( approximately 100 nM to approximately 2 microM); 2), M(2)R activation strongly reduces the beta(1)AR-induced increases in caveolar cAMP, with less effect on bulk cAMP; and 3), during weak beta(1)AR stimulation, M(2)R activation not only reduces caveolar cAMP, but also produces a rebound increase in caveolar cAMP following termination of M(2)R activity. We conclude that compartmentation of cAMP can provide a quantitative explanation for several aspects of cardiac signaling.
</para>
<para>
The original paper reference is cited below:
</para>
<para>
Compartmentation of cAMP signaling in cardiac myocytes: a computational study, Radu V. Iancu, Stephen W. Jones, Robert D. Harvey, 2007, <emphasis>Biophysical Journal</emphasis>, volume 92, 3317-3331. <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17293406&query_hl=1&itool=pubmed_docsum">PubMed ID: 17293406</ulink>
</para>
<informalfigure float="0" id="fig_pathway_diagram">
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<imageobject>
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<title>model diagram</title>
</objectinfo>
<imagedata fileref="iancu_2007.png"/>
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<caption>A schematic diagram of the signalling pathway.</caption>
</informalfigure>
</sect1>
</article>
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<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Gs_alpha_GTP</ci>
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<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci>RG</ci>
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<times/>
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<apply>
<times/>
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<ci>k_hydr</ci>
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<minus/>
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<plus/>
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<times/>
<ci>LRG</ci>
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<apply>
<times/>
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<ci>k_reas</ci>
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<apply>
<eq/>
<apply>
<diff/>
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<ci>time</ci>
</bvar>
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<minus/>
<apply>
<times/>
<ci>Gs_alpha_GTP</ci>
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<times/>
<ci>Gs_alpha_GDP</ci>
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<ci>k_reas</ci>
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</apply>
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<apply>
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<ci>Gs_alpha_beta_gamma</ci>
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<minus/>
<apply>
<minus/>
<ci>Gs_Total</ci>
<ci>Gs_alpha_GTP</ci>
</apply>
<ci>Gs_alpha_GDP</ci>
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</apply>
</math>
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<variable name="Gi_alpha_beta_gamma" units="uM" public_interface="out"/>
<variable name="Gi_Total" units="uM" initial_value="1" public_interface="out"/>
<variable name="time" units="second" public_interface="in"/>
<variable name="RG" units="uM" public_interface="in"/>
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<variable name="k_hydr" units="per_sec" public_interface="in"/>
<variable name="k_reas" units="per_uM_per_sec" public_interface="in"/>
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<eq/>
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<diff/>
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<minus/>
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<plus/>
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<times/>
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<times/>
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<minus/>
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<times/>
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<times/>
<ci>Gi_alpha_GDP</ci>
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<minus/>
<apply>
<minus/>
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<variable name="dcAMP_AC_56_dt" units="uM_per_sec" public_interface="out"/>
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<eq/>
<ci>k_AC56</ci>
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<times/>
<apply>
<divide/>
<apply>
<times/>
<apply>
<plus/>
<cn cellml:units="dimensionless">0.7</cn>
<apply>
<divide/>
<apply>
<times/>
<cn cellml:units="dimensionless">3.8234</cn>
<apply>
<power/>
<apply>
<divide/>
<ci>Gs_alpha_GTP</ci>
<cn cellml:units="uM">1</cn>
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<cn cellml:units="dimensionless">0.9787</cn>
</apply>
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<apply>
<plus/>
<cn cellml:units="dimensionless">0.1986</cn>
<apply>
<power/>
<apply>
<divide/>
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<cn cellml:units="uM">1</cn>
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<cn cellml:units="dimensionless">0.9787</cn>
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</apply>
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<apply>
<plus/>
<cn cellml:units="dimensionless">1</cn>
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<divide/>
<apply>
<times/>
<apply>
<divide/>
<cn cellml:units="dimensionless">1</cn>
<cn cellml:units="dimensionless">1.4432</cn>
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<apply>
<minus/>
<cn cellml:units="dimensionless">1.0061</cn>
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<apply>
<power/>
<apply>
<divide/>
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<plus/>
<cn cellml:units="dimensionless">0.1918</cn>
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<power/>
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<divide/>
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<cn cellml:units="dimensionless">0.8356</cn>
</apply>
</apply>
</apply>
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<ci>MW_AC56</ci>
</apply>
<cn cellml:units="kDa">60</cn>
</apply>
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<eq/>
<ci>dcAMP_AC_56_dt</ci>
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<divide/>
<apply>
<times/>
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<ci>ATP</ci>
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<apply>
<plus/>
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<ci>ATP</ci>
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</math>
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<variable name="dcAMP_AC_47_ecav_dt" units="uM_per_sec" public_interface="out"/>
<variable name="Gs_alpha_GTP" units="uM" public_interface="in"/>
<variable name="Gi_beta_gamma" units="uM" public_interface="in"/>
<variable name="k_AC47_ecav" units="per_sec"/>
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<eq/>
<ci>k_AC47_ecav</ci>
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<times/>
<apply>
<divide/>
<apply>
<times/>
<apply>
<plus/>
<cn cellml:units="dimensionless">0.063</cn>
<apply>
<divide/>
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<times/>
<cn cellml:units="dimensionless">2.01</cn>
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<power/>
<apply>
<times/>
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<plus/>
<cn cellml:units="dimensionless">31.544</cn>
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<power/>
<apply>
<times/>
<ci>Gs_alpha_GTP</ci>
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<plus/>
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<divide/>
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<times/>
<apply>
<divide/>
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<cn cellml:units="dimensionless">49.1</cn>
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<power/>
<apply>
<times/>
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<apply>
<plus/>
<cn cellml:units="dimensionless">25.44</cn>
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<power/>
<apply>
<times/>
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</apply>
<ci>MW_AC47</ci>
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<eq/>
<ci>dcAMP_AC_47_ecav_dt</ci>
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<divide/>
<apply>
<times/>
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<apply>
<plus/>
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<variable name="dcAMP_AC_47_cyt_dt" units="uM_per_sec" public_interface="out"/>
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<eq/>
<ci>dcAMP_AC_47_cyt_dt</ci>
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<divide/>
<apply>
<times/>
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<apply>
<plus/>
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</apply>
</apply>
</apply>
</math>
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<variable name="dcAMP_cav_PDE2_dt" units="uM_per_sec" public_interface="out"/>
<variable name="dcAMP_cav_PDE3_dt" units="uM_per_sec" public_interface="out"/>
<variable name="dcAMP_cav_PDE4_dt" units="uM_per_sec" public_interface="out"/>
<variable name="cAMP_cav" units="uM" public_interface="in"/>
<variable name="PDE2" units="uM" initial_value="4.5"/>
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<variable name="PDE3" units="uM" initial_value="5.6"/>
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<variable name="PDE4" units="uM" initial_value="2"/>
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<variable name="Km_PDE4" units="uM" public_interface="in"/>
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<eq/>
<ci>dcAMP_cav_PDE2_dt</ci>
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<divide/>
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<times/>
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<ci>cAMP_cav</ci>
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<apply>
<plus/>
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</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>dcAMP_cav_PDE3_dt</ci>
<apply>
<divide/>
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<times/>
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<ci>cAMP_cav</ci>
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<apply>
<plus/>
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</apply>
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<apply>
<eq/>
<ci>dcAMP_cav_PDE4_dt</ci>
<apply>
<divide/>
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<times/>
<ci>k_PDE4</ci>
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<plus/>
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<component xmlns="http://www.cellml.org/cellml/1.0#" name="extracaveolar_PDE_module">
<variable name="dcAMP_ecav_PDE2_dt" units="uM_per_sec" public_interface="out"/>
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<variable name="cAMP_ecav" units="uM" public_interface="in"/>
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<variable name="Km_PDE2" units="uM" public_interface="in"/>
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<variable name="Km_PDE4" units="uM" public_interface="in"/>
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<eq/>
<ci>dcAMP_ecav_PDE2_dt</ci>
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<divide/>
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<times/>
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<plus/>
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</apply>
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<eq/>
<ci>dcAMP_ecav_PDE4_dt</ci>
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<divide/>
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<times/>
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<plus/>
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<component xmlns="http://www.cellml.org/cellml/1.0#" name="bulk_cytoplasmic_PDE_module">
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<variable name="dcAMP_cyt_PDE3_dt" units="uM_per_sec" public_interface="out"/>
<variable name="dcAMP_cyt_PDE4_dt" units="uM_per_sec" public_interface="out"/>
<variable name="cAMP_cyt" units="uM" public_interface="in"/>
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<variable name="Km_PDE4" units="uM" public_interface="in"/>
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<eq/>
<ci>dcAMP_cyt_PDE2_dt</ci>
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<divide/>
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<times/>
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<plus/>
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<eq/>
<ci>dcAMP_cyt_PDE3_dt</ci>
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<divide/>
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<times/>
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<apply>
<plus/>
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<eq/>
<ci>dcAMP_cyt_PDE4_dt</ci>
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<divide/>
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<times/>
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<plus/>
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</apply>
</math>
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<component xmlns="http://www.cellml.org/cellml/1.0#" name="cAMP_flux_module">
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<variable name="V_ecav" units="liter"/>
<variable name="V_cyt" units="liter"/>
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<variable name="dcAMP_AC_56_dt" units="uM_per_sec" public_interface="in"/>
<variable name="dcAMP_AC_47_ecav_dt" units="uM_per_sec" public_interface="in"/>
<variable name="dcAMP_AC_47_cyt_dt" units="uM_per_sec" public_interface="in"/>
<variable name="dcAMP_cav_PDE2_dt" units="uM_per_sec" public_interface="in"/>
<variable name="dcAMP_cav_PDE3_dt" units="uM_per_sec" public_interface="in"/>
<variable name="dcAMP_cav_PDE4_dt" units="uM_per_sec" public_interface="in"/>
<variable name="dcAMP_ecav_PDE2_dt" units="uM_per_sec" public_interface="in"/>
<variable name="dcAMP_ecav_PDE4_dt" units="uM_per_sec" public_interface="in"/>
<variable name="dcAMP_cyt_PDE2_dt" units="uM_per_sec" public_interface="in"/>
<variable name="dcAMP_cyt_PDE3_dt" units="uM_per_sec" public_interface="in"/>
<variable name="dcAMP_cyt_PDE4_dt" units="uM_per_sec" public_interface="in"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>V_cav</ci>
<apply>
<times/>
<cn cellml:units="dimensionless">0.01</cn>
<ci>V_cell</ci>
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</apply>
<apply>
<eq/>
<ci>V_ecav</ci>
<apply>
<times/>
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</apply>
<apply>
<eq/>
<ci>V_cyt</ci>
<apply>
<times/>
<cn cellml:units="dimensionless">0.5</cn>
<ci>V_cell</ci>
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</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
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<apply>
<minus/>
<apply>
<minus/>
<apply>
<minus/>
<ci>dcAMP_AC_56_dt</ci>
<apply>
<plus/>
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<ci>dcAMP_cav_PDE3_dt</ci>
<ci>dcAMP_cav_PDE4_dt</ci>
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<apply>
<divide/>
<apply>
<times/>
<ci>J_cav_ecav</ci>
<apply>
<minus/>
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<ci>cAMP_ecav</ci>
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<ci>V_cav</ci>
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<apply>
<divide/>
<apply>
<times/>
<ci>J_cav_cyt</ci>
<apply>
<minus/>
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<ci>V_cav</ci>
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</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
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<apply>
<minus/>
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<plus/>
<apply>
<minus/>
<ci>dcAMP_AC_47_ecav_dt</ci>
<apply>
<plus/>
<ci>dcAMP_ecav_PDE2_dt</ci>
<ci>dcAMP_ecav_PDE4_dt</ci>
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<apply>
<divide/>
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<times/>
<ci>J_cav_ecav</ci>
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