<?xml version="1.0"?>
<!--
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/
--><model xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" cmeta:id="iancu_jones_harvey_2007" name="iancu_jones_harvey_2007">
<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">
<mediaobject>
<imageobject>
<objectinfo>
<title>model diagram</title>
</objectinfo>
<imagedata fileref="iancu_2007.png"/>
</imageobject>
</mediaobject>
<caption>A schematic diagram of the signalling pathway.</caption>
</informalfigure>
</sect1>
</article>
</documentation> <units name="uM">
<unit prefix="micro" units="mole"/>
<unit exponent="-1" units="liter"/>
</units>
<units name="per_uM">
<unit exponent="-1" units="uM"/>
</units>
<units name="per_sec">
<unit exponent="-1" units="second"/>
</units>
<units name="uM_per_sec">
<unit units="uM"/>
<unit exponent="-1" units="second"/>
</units>
<units name="per_uM_per_sec">
<unit exponent="-1" units="uM"/>
<unit exponent="-1" units="second"/>
</units>
<units name="liters_per_second">
<unit units="liter"/>
<unit exponent="-1" units="second"/>
</units>
<units name="kDa">
<unit prefix="kilo" units="gram"/>
<unit exponent="-1" units="mole"/>
</units>
<component name="environment">
<variable cmeta:id="environment_time" name="time" public_interface="out" units="second"/>
</component>
<component name="beta_1_adrenergic_parameters">
<variable name="L_iso" public_interface="out" units="uM"/>
<variable initial_value="0.035" name="K_H" public_interface="out" units="uM"/>
<variable initial_value="0.386" name="K_L" public_interface="out" units="uM"/>
<variable initial_value="8.809" name="K_C" public_interface="out" units="uM"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>L_iso</ci>
<piecewise>
<piece>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="uM">1</cn>
<apply>
<and/>
<apply>
<gt/>
<ci>time</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">120</cn>
</apply>
<apply>
<leq/>
<ci>time</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">720</cn>
</apply>
</apply>
</piece>
<otherwise>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="uM">1</cn>
</otherwise>
</piecewise>
</apply>
</math>
</component>
<component name="muscarinic_parameters">
<variable name="L_ach" public_interface="out" units="uM"/>
<variable initial_value="0.16" name="K_H" public_interface="out" units="uM"/>
<variable initial_value="11" name="K_L" public_interface="out" units="uM"/>
<variable initial_value="30" name="K_C" public_interface="out" units="uM"/>
<variable name="time" public_interface="in" units="second"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>L_ach</ci>
<piecewise>
<piece>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="uM">0</cn>
<apply>
<and/>
<apply>
<gt/>
<ci>time</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">240</cn>
</apply>
<apply>
<leq/>
<ci>time</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="second">540</cn>
</apply>
</apply>
</piece>
<otherwise>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="uM">0</cn>
</otherwise>
</piecewise>
</apply>
</math>
</component>
<component name="PDE_parameters">
<variable initial_value="20" name="k_PDE2" public_interface="out" units="per_sec"/>
<variable initial_value="50" name="Km_PDE2" public_interface="out" units="uM"/>
<variable initial_value="1.25" name="k_PDE3" public_interface="out" units="per_sec"/>
<variable initial_value="0.08" name="Km_PDE3" public_interface="out" units="uM"/>
<variable initial_value="2.5" name="k_PDE4" public_interface="out" units="per_sec"/>
<variable initial_value="2.2" name="Km_PDE4" public_interface="out" units="uM"/>
</component>
<component name="G_s_parameters">
<variable initial_value="5" name="k_act1" public_interface="out" units="per_sec"/>
<variable initial_value="0.1" name="k_act2" public_interface="out" units="per_sec"/>
<variable initial_value="0.8" name="k_hydr" public_interface="out" units="per_sec"/>
<variable initial_value="1.21e3" name="k_reas" public_interface="out" units="per_uM_per_sec"/>
</component>
<component name="G_i_parameters">
<variable initial_value="2.5" name="k_act1" public_interface="out" units="per_sec"/>
<variable initial_value="0.05" name="k_act2" public_interface="out" units="per_sec"/>
<variable initial_value="0.8" name="k_hydr" public_interface="out" units="per_sec"/>
<variable initial_value="1.21e3" name="k_reas" public_interface="out" units="per_uM_per_sec"/>
</component>
<component name="caveolar_beta_1_adrenergic_receptor_module">
<variable name="R" units="uM"/>
<variable name="LR" units="uM"/>
<variable name="LRG" public_interface="out" units="uM"/>
<variable name="RG" public_interface="out" units="uM"/>
<variable initial_value="0.633" name="R_Total" units="uM"/>
<variable name="G" public_interface="in" units="uM"/>
<variable name="L_iso" public_interface="in" units="uM"/>
<variable name="K_H" public_interface="in" units="uM"/>
<variable name="K_L" public_interface="in" units="uM"/>
<variable name="K_C" public_interface="in" units="uM"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>R</ci>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<minus/>
<ci>R_Total</ci>
<ci>LR</ci>
</apply>
<ci>LRG</ci>
</apply>
<ci>RG</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>LR</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>L_iso</ci>
<ci>R</ci>
</apply>
<ci>K_L</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>LRG</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>L_iso</ci>
<ci>R</ci>
<ci>G</ci>
</apply>
<apply>
<times/>
<ci>K_H</ci>
<ci>K_C</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>RG</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>R</ci>
<ci>G</ci>
</apply>
<ci>K_C</ci>
</apply>
</apply>
</math>
</component>
<component name="caveolar_muscarinic_receptor_module">
<variable name="R" units="uM"/>
<variable name="LR" units="uM"/>
<variable name="LRG" public_interface="out" units="uM"/>
<variable name="RG" public_interface="out" units="uM"/>
<variable initial_value="0.633" name="R_Total" units="uM"/>
<variable name="G" public_interface="in" units="uM"/>
<variable name="L_ach" public_interface="in" units="uM"/>
<variable name="K_H" public_interface="in" units="uM"/>
<variable name="K_L" public_interface="in" units="uM"/>
<variable name="K_C" public_interface="in" units="uM"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>R</ci>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<minus/>
<ci>R_Total</ci>
<ci>LR</ci>
</apply>
<ci>LRG</ci>
</apply>
<ci>RG</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>LR</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>L_ach</ci>
<ci>R</ci>
</apply>
<ci>K_L</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>LRG</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>L_ach</ci>
<ci>R</ci>
<ci>G</ci>
</apply>
<apply>
<times/>
<ci>K_H</ci>
<ci>K_C</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>RG</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>R</ci>
<ci>G</ci>
</apply>
<ci>K_C</ci>
</apply>
</apply>
</math>
</component>
<component name="caveolar_G_s_protein_activation_module">
<variable initial_value="0.041983438" name="Gs_alpha_GTP" public_interface="out" units="uM"/>
<variable initial_value="0.042634499" name="Gs_beta_gamma" public_interface="out" units="uM"/>
<variable initial_value="0.000651061" name="Gs_alpha_GDP" public_interface="out" units="uM"/>
<variable name="Gs_alpha_beta_gamma" public_interface="out" units="uM"/>
<variable cmeta:id="caveolar_G_s_protein_activation_module_Gs_Total" initial_value="10" name="Gs_Total" public_interface="out" units="uM"/>
<variable name="time" public_interface="in" units="second"/>
<variable name="RG" public_interface="in" units="uM"/>
<variable name="LRG" public_interface="in" units="uM"/>
<variable name="k_act1" public_interface="in" units="per_sec"/>
<variable name="k_act2" public_interface="in" units="per_sec"/>
<variable name="k_hydr" public_interface="in" units="per_sec"/>
<variable name="k_reas" public_interface="in" units="per_uM_per_sec"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Gs_alpha_GTP</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci>RG</ci>
<ci>k_act2</ci>
</apply>
<apply>
<times/>
<ci>LRG</ci>
<ci>k_act1</ci>
</apply>
</apply>
<apply>
<times/>
<ci>Gs_alpha_GTP</ci>
<ci>k_hydr</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Gs_beta_gamma</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci>RG</ci>
<ci>k_act2</ci>
</apply>
<apply>
<times/>
<ci>LRG</ci>
<ci>k_act1</ci>
</apply>
</apply>
<apply>
<times/>
<ci>Gs_alpha_GDP</ci>
<ci>Gs_beta_gamma</ci>
<ci>k_reas</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Gs_alpha_GDP</ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>Gs_alpha_GTP</ci>
<ci>k_hydr</ci>
</apply>
<apply>
<times/>
<ci>Gs_alpha_GDP</ci>
<ci>Gs_beta_gamma</ci>
<ci>k_reas</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>Gs_alpha_beta_gamma</ci>
<apply>
<minus/>
<apply>
<minus/>
<ci>Gs_Total</ci>
<ci>Gs_alpha_GTP</ci>
</apply>
<ci>Gs_alpha_GDP</ci>
</apply>
</apply>
</math>
</component>
<component name="caveolar_G_i_protein_activation_module">
<variable initial_value="0.012644961" name="Gi_alpha_GTP" public_interface="out" units="uM"/>
<variable initial_value="0.013274751" name="Gi_beta_gamma" public_interface="out" units="uM"/>
<variable initial_value="0.00062979" name="Gi_alpha_GDP" public_interface="out" units="uM"/>
<variable name="Gi_alpha_beta_gamma" public_interface="out" units="uM"/>
<variable cmeta:id="caveolar_G_i_protein_activation_module_Gi_Total" initial_value="20" name="Gi_Total" public_interface="out" units="uM"/>
<variable name="time" public_interface="in" units="second"/>
<variable name="RG" public_interface="in" units="uM"/>
<variable name="LRG" public_interface="in" units="uM"/>
<variable name="k_act1" public_interface="in" units="per_sec"/>
<variable name="k_act2" public_interface="in" units="per_sec"/>
<variable name="k_hydr" public_interface="in" units="per_sec"/>
<variable name="k_reas" public_interface="in" units="per_uM_per_sec"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Gi_alpha_GTP</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci>RG</ci>
<ci>k_act2</ci>
</apply>
<apply>
<times/>
<ci>LRG</ci>
<ci>k_act1</ci>
</apply>
</apply>
<apply>
<times/>
<ci>Gi_alpha_GTP</ci>
<ci>k_hydr</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Gi_beta_gamma</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci>RG</ci>
<ci>k_act2</ci>
</apply>
<apply>
<times/>
<ci>LRG</ci>
<ci>k_act1</ci>
</apply>
</apply>
<apply>
<times/>
<ci>Gi_alpha_GDP</ci>
<ci>Gi_beta_gamma</ci>
<ci>k_reas</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Gi_alpha_GDP</ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>Gi_alpha_GTP</ci>
<ci>k_hydr</ci>
</apply>
<apply>
<times/>
<ci>Gi_alpha_GDP</ci>
<ci>Gi_beta_gamma</ci>
<ci>k_reas</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>Gi_alpha_beta_gamma</ci>
<apply>
<minus/>
<apply>
<minus/>
<ci>Gi_Total</ci>
<ci>Gi_alpha_GTP</ci>
</apply>
<ci>Gi_alpha_GDP</ci>
</apply>
</apply>
</math>
</component>
<component name="extracaveolar_beta_1_adrenergic_receptor_module">
<variable name="R" units="uM"/>
<variable name="LR" units="uM"/>
<variable name="LRG" public_interface="out" units="uM"/>
<variable name="RG" public_interface="out" units="uM"/>
<variable initial_value="0.633" name="R_Total" units="uM"/>
<variable name="G" public_interface="in" units="uM"/>
<variable name="L_iso" public_interface="in" units="uM"/>
<variable name="K_H" public_interface="in" units="uM"/>
<variable name="K_L" public_interface="in" units="uM"/>
<variable name="K_C" public_interface="in" units="uM"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>R</ci>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<minus/>
<ci>R_Total</ci>
<ci>LR</ci>
</apply>
<ci>LRG</ci>
</apply>
<ci>RG</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>LR</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>L_iso</ci>
<ci>R</ci>
</apply>
<ci>K_L</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>LRG</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>L_iso</ci>
<ci>R</ci>
<ci>G</ci>
</apply>
<apply>
<times/>
<ci>K_H</ci>
<ci>K_C</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>RG</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>R</ci>
<ci>G</ci>
</apply>
<ci>K_C</ci>
</apply>
</apply>
</math>
</component>
<component name="extracaveolar_muscarinic_receptor_module">
<variable name="R" units="uM"/>
<variable name="LR" units="uM"/>
<variable name="LRG" public_interface="out" units="uM"/>
<variable name="RG" public_interface="out" units="uM"/>
<variable initial_value="0.633" name="R_Total" units="uM"/>
<variable name="G" public_interface="in" units="uM"/>
<variable name="L_ach" public_interface="in" units="uM"/>
<variable name="K_H" public_interface="in" units="uM"/>
<variable name="K_L" public_interface="in" units="uM"/>
<variable name="K_C" public_interface="in" units="uM"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>R</ci>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<minus/>
<ci>R_Total</ci>
<ci>LR</ci>
</apply>
<ci>LRG</ci>
</apply>
<ci>RG</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>LR</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>L_ach</ci>
<ci>R</ci>
</apply>
<ci>K_L</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>LRG</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>L_ach</ci>
<ci>R</ci>
<ci>G</ci>
</apply>
<apply>
<times/>
<ci>K_H</ci>
<ci>K_C</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>RG</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>R</ci>
<ci>G</ci>
</apply>
<ci>K_C</ci>
</apply>
</apply>
</math>
</component>
<component name="extracaveolar_G_s_protein_activation_module">
<variable initial_value="0.083866891" name="Gs_alpha_GTP" public_interface="out" units="uM"/>
<variable initial_value="0.084522918" name="Gs_beta_gamma" public_interface="out" units="uM"/>
<variable initial_value="0.000656025" name="Gs_alpha_GDP" public_interface="out" units="uM"/>
<variable name="Gs_alpha_beta_gamma" public_interface="out" units="uM"/>
<variable initial_value="10" name="Gs_Total" public_interface="out" units="uM"/>
<variable name="time" public_interface="in" units="second"/>
<variable name="RG" public_interface="in" units="uM"/>
<variable name="LRG" public_interface="in" units="uM"/>
<variable name="k_act1" public_interface="in" units="per_sec"/>
<variable name="k_act2" public_interface="in" units="per_sec"/>
<variable name="k_hydr" public_interface="in" units="per_sec"/>
<variable name="k_reas" public_interface="in" units="per_uM_per_sec"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Gs_alpha_GTP</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci>RG</ci>
<ci>k_act2</ci>
</apply>
<apply>
<times/>
<ci>LRG</ci>
<ci>k_act1</ci>
</apply>
</apply>
<apply>
<times/>
<ci>Gs_alpha_GTP</ci>
<ci>k_hydr</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Gs_beta_gamma</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci>RG</ci>
<ci>k_act2</ci>
</apply>
<apply>
<times/>
<ci>LRG</ci>
<ci>k_act1</ci>
</apply>
</apply>
<apply>
<times/>
<ci>Gs_alpha_GDP</ci>
<ci>Gs_beta_gamma</ci>
<ci>k_reas</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Gs_alpha_GDP</ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>Gs_alpha_GTP</ci>
<ci>k_hydr</ci>
</apply>
<apply>
<times/>
<ci>Gs_alpha_GDP</ci>
<ci>Gs_beta_gamma</ci>
<ci>k_reas</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>Gs_alpha_beta_gamma</ci>
<apply>
<minus/>
<apply>
<minus/>
<ci>Gs_Total</ci>
<ci>Gs_alpha_GTP</ci>
</apply>
<ci>Gs_alpha_GDP</ci>
</apply>
</apply>
</math>
</component>
<component name="extracaveolar_G_i_protein_activation_module">
<variable initial_value="0.001018705" name="Gi_alpha_GTP" public_interface="out" units="uM"/>
<variable initial_value="0.001475253" name="Gi_beta_gamma" public_interface="out" units="uM"/>
<variable initial_value="0.000456548" name="Gi_alpha_GDP" public_interface="out" units="uM"/>
<variable name="Gi_alpha_beta_gamma" public_interface="out" units="uM"/>
<variable initial_value="1" name="Gi_Total" public_interface="out" units="uM"/>
<variable name="time" public_interface="in" units="second"/>
<variable name="RG" public_interface="in" units="uM"/>
<variable name="LRG" public_interface="in" units="uM"/>
<variable name="k_act1" public_interface="in" units="per_sec"/>
<variable name="k_act2" public_interface="in" units="per_sec"/>
<variable name="k_hydr" public_interface="in" units="per_sec"/>
<variable name="k_reas" public_interface="in" units="per_uM_per_sec"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Gi_alpha_GTP</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci>RG</ci>
<ci>k_act2</ci>
</apply>
<apply>
<times/>
<ci>LRG</ci>
<ci>k_act1</ci>
</apply>
</apply>
<apply>
<times/>
<ci>Gi_alpha_GTP</ci>
<ci>k_hydr</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Gi_beta_gamma</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<times/>
<ci>RG</ci>
<ci>k_act2</ci>
</apply>
<apply>
<times/>
<ci>LRG</ci>
<ci>k_act1</ci>
</apply>
</apply>
<apply>
<times/>
<ci>Gi_alpha_GDP</ci>
<ci>Gi_beta_gamma</ci>
<ci>k_reas</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Gi_alpha_GDP</ci>
</apply>
<apply>
<minus/>
<apply>
<times/>
<ci>Gi_alpha_GTP</ci>
<ci>k_hydr</ci>
</apply>
<apply>
<times/>
<ci>Gi_alpha_GDP</ci>
<ci>Gi_beta_gamma</ci>
<ci>k_reas</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>Gi_alpha_beta_gamma</ci>
<apply>
<minus/>
<apply>
<minus/>
<ci>Gi_Total</ci>
<ci>Gi_alpha_GTP</ci>
</apply>
<ci>Gi_alpha_GDP</ci>
</apply>
</apply>
</math>
</component>
<component name="AC56_module">
<variable name="dcAMP_AC_56_dt" public_interface="out" units="uM_per_sec"/>
<variable name="Gs_alpha_GTP" public_interface="in" units="uM"/>
<variable name="Gi_alpha_GTP" public_interface="in" units="uM"/>
<variable name="k_AC56" units="per_sec"/>
<variable cmeta:id="AC56_module_AC_56" initial_value="3.379" name="AC_56" units="uM"/>
<variable initial_value="500" name="AF56" units="dimensionless"/>
<variable initial_value="130" name="MW_AC56" units="kDa"/>
<variable initial_value="5000" name="ATP" units="uM"/>
<variable initial_value="315" name="Km_ATP" units="uM"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>k_AC56</ci>
<apply>
<times/>
<apply>
<divide/>
<apply>
<times/>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.7</cn>
<apply>
<divide/>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">3.8234</cn>
<apply>
<power/>
<apply>
<divide/>
<ci>Gs_alpha_GTP</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="uM">1</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.9787</cn>
</apply>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.1986</cn>
<apply>
<power/>
<apply>
<divide/>
<ci>Gs_alpha_GTP</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="uM">1</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.9787</cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<divide/>
<apply>
<times/>
<apply>
<divide/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1.4432</cn>
</apply>
<apply>
<minus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1.0061</cn>
</apply>
<apply>
<power/>
<apply>
<divide/>
<ci>Gi_alpha_GTP</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="uM">1</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.8356</cn>
</apply>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.1918</cn>
<apply>
<power/>
<apply>
<divide/>
<ci>Gi_alpha_GTP</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="uM">1</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.8356</cn>
</apply>
</apply>
</apply>
</apply>
<ci>MW_AC56</ci>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="kDa">60</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_sec">0.001</cn>
</apply>
</apply>
<apply>
<eq/>
<ci>dcAMP_AC_56_dt</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>k_AC56</ci>
<ci>AC_56</ci>
<ci>AF56</ci>
<ci>ATP</ci>
</apply>
<apply>
<plus/>
<ci>Km_ATP</ci>
<ci>ATP</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="AC47_ecav_module">
<variable name="dcAMP_AC_47_ecav_dt" public_interface="out" units="uM_per_sec"/>
<variable name="Gs_alpha_GTP" public_interface="in" units="uM"/>
<variable name="Gi_beta_gamma" public_interface="in" units="uM"/>
<variable name="k_AC47_ecav" units="per_sec"/>
<variable initial_value="0.2" name="AC_47_ecav" units="uM"/>
<variable initial_value="130" name="AF47" units="dimensionless"/>
<variable initial_value="130" name="MW_AC47" units="kDa"/>
<variable initial_value="5000" name="ATP" units="uM"/>
<variable initial_value="315" name="Km_ATP" units="uM"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>k_AC47_ecav</ci>
<apply>
<times/>
<apply>
<divide/>
<apply>
<times/>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.063</cn>
<apply>
<divide/>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">2.01</cn>
<apply>
<power/>
<apply>
<times/>
<ci>Gs_alpha_GTP</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_uM">1000</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1.0043</cn>
</apply>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">31.544</cn>
<apply>
<power/>
<apply>
<times/>
<ci>Gs_alpha_GTP</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_uM">1000</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1.0043</cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<apply>
<divide/>
<apply>
<times/>
<apply>
<divide/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">1</cn>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">3.01</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">49.1</cn>
<apply>
<power/>
<apply>
<times/>
<ci>Gi_beta_gamma</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_uM">1000</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.8921</cn>
</apply>
</apply>
<apply>
<plus/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">25.44</cn>
<apply>
<power/>
<apply>
<times/>
<ci>Gi_beta_gamma</ci>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_uM">1000</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.8921</cn>
</apply>
</apply>
</apply>
</apply>
<ci>MW_AC47</ci>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="kDa">60</cn>
</apply>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="per_sec">0.001</cn>
</apply>
</apply>
<apply>
<eq/>
<ci>dcAMP_AC_47_ecav_dt</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>k_AC47_ecav</ci>
<ci>AC_47_ecav</ci>
<ci>AF47</ci>
<ci>ATP</ci>
</apply>
<apply>
<plus/>
<ci>Km_ATP</ci>
<ci>ATP</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="AC47_cyt_module">
<variable name="dcAMP_AC_47_cyt_dt" public_interface="out" units="uM_per_sec"/>
<variable initial_value="1.08e-3" name="k_AC47_cyt" units="per_sec"/>
<variable initial_value="0.136" name="AC_47_cyt" units="uM"/>
<variable initial_value="130" name="AF47" units="dimensionless"/>
<variable initial_value="5000" name="ATP" units="uM"/>
<variable initial_value="315" name="Km_ATP" units="uM"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>dcAMP_AC_47_cyt_dt</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>k_AC47_cyt</ci>
<ci>AC_47_cyt</ci>
<ci>AF47</ci>
<ci>ATP</ci>
</apply>
<apply>
<plus/>
<ci>Km_ATP</ci>
<ci>ATP</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="caveolar_PDE_module">
<variable name="dcAMP_cav_PDE2_dt" public_interface="out" units="uM_per_sec"/>
<variable name="dcAMP_cav_PDE3_dt" public_interface="out" units="uM_per_sec"/>
<variable name="dcAMP_cav_PDE4_dt" public_interface="out" units="uM_per_sec"/>
<variable name="cAMP_cav" public_interface="in" units="uM"/>
<variable initial_value="4.5" name="PDE2" units="uM"/>
<variable name="k_PDE2" public_interface="in" units="per_sec"/>
<variable name="Km_PDE2" public_interface="in" units="uM"/>
<variable initial_value="5.6" name="PDE3" units="uM"/>
<variable name="k_PDE3" public_interface="in" units="per_sec"/>
<variable name="Km_PDE3" public_interface="in" units="uM"/>
<variable initial_value="2" name="PDE4" units="uM"/>
<variable name="k_PDE4" public_interface="in" units="per_sec"/>
<variable name="Km_PDE4" public_interface="in" units="uM"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>dcAMP_cav_PDE2_dt</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>k_PDE2</ci>
<ci>PDE2</ci>
<ci>cAMP_cav</ci>
</apply>
<apply>
<plus/>
<ci>Km_PDE2</ci>
<ci>cAMP_cav</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>dcAMP_cav_PDE3_dt</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>k_PDE3</ci>
<ci>PDE3</ci>
<ci>cAMP_cav</ci>
</apply>
<apply>
<plus/>
<ci>Km_PDE3</ci>
<ci>cAMP_cav</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>dcAMP_cav_PDE4_dt</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>k_PDE4</ci>
<ci>PDE4</ci>
<ci>cAMP_cav</ci>
</apply>
<apply>
<plus/>
<ci>Km_PDE4</ci>
<ci>cAMP_cav</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="extracaveolar_PDE_module">
<variable name="dcAMP_ecav_PDE2_dt" public_interface="out" units="uM_per_sec"/>
<variable name="dcAMP_ecav_PDE4_dt" public_interface="out" units="uM_per_sec"/>
<variable name="cAMP_ecav" public_interface="in" units="uM"/>
<variable initial_value="0.02" name="PDE2" units="uM"/>
<variable name="k_PDE2" public_interface="in" units="per_sec"/>
<variable name="Km_PDE2" public_interface="in" units="uM"/>
<variable initial_value="0.16" name="PDE4" units="uM"/>
<variable name="k_PDE4" public_interface="in" units="per_sec"/>
<variable name="Km_PDE4" public_interface="in" units="uM"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>dcAMP_ecav_PDE2_dt</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>k_PDE2</ci>
<ci>PDE2</ci>
<ci>cAMP_ecav</ci>
</apply>
<apply>
<plus/>
<ci>Km_PDE2</ci>
<ci>cAMP_ecav</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>dcAMP_ecav_PDE4_dt</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>k_PDE4</ci>
<ci>PDE4</ci>
<ci>cAMP_ecav</ci>
</apply>
<apply>
<plus/>
<ci>Km_PDE4</ci>
<ci>cAMP_ecav</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="bulk_cytoplasmic_PDE_module">
<variable name="dcAMP_cyt_PDE2_dt" public_interface="out" units="uM_per_sec"/>
<variable name="dcAMP_cyt_PDE3_dt" public_interface="out" units="uM_per_sec"/>
<variable name="dcAMP_cyt_PDE4_dt" public_interface="out" units="uM_per_sec"/>
<variable name="cAMP_cyt" public_interface="in" units="uM"/>
<variable cmeta:id="bulk_cytoplasmic_PDE_module_PDE2" initial_value="5e-3" name="PDE2" units="uM"/>
<variable name="k_PDE2" public_interface="in" units="per_sec"/>
<variable name="Km_PDE2" public_interface="in" units="uM"/>
<variable cmeta:id="bulk_cytoplasmic_PDE_module_PDE3" initial_value="7.5e-3" name="PDE3" units="uM"/>
<variable name="k_PDE3" public_interface="in" units="per_sec"/>
<variable name="Km_PDE3" public_interface="in" units="uM"/>
<variable cmeta:id="bulk_cytoplasmic_PDE_module_PDE4" initial_value="5e-3" name="PDE4" units="uM"/>
<variable name="k_PDE4" public_interface="in" units="per_sec"/>
<variable name="Km_PDE4" public_interface="in" units="uM"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>dcAMP_cyt_PDE2_dt</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>k_PDE2</ci>
<ci>PDE2</ci>
<ci>cAMP_cyt</ci>
</apply>
<apply>
<plus/>
<ci>Km_PDE2</ci>
<ci>cAMP_cyt</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>dcAMP_cyt_PDE3_dt</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>k_PDE3</ci>
<ci>PDE3</ci>
<ci>cAMP_cyt</ci>
</apply>
<apply>
<plus/>
<ci>Km_PDE3</ci>
<ci>cAMP_cyt</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<ci>dcAMP_cyt_PDE4_dt</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>k_PDE4</ci>
<ci>PDE4</ci>
<ci>cAMP_cyt</ci>
</apply>
<apply>
<plus/>
<ci>Km_PDE4</ci>
<ci>cAMP_cyt</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component name="cAMP_flux_module">
<variable cmeta:id="cAMP_flux_module_cAMP_cav" initial_value="0.11750433" name="cAMP_cav" public_interface="out" units="uM"/>
<variable cmeta:id="cAMP_flux_module_cAMP_ecav" initial_value="1.092200547" name="cAMP_ecav" public_interface="out" units="uM"/>
<variable cmeta:id="cAMP_flux_module_cAMP_cyt" initial_value="0.992583576" name="cAMP_cyt" public_interface="out" units="uM"/>
<variable name="time" public_interface="in" units="second"/>
<variable name="V_cav" units="liter"/>
<variable name="V_ecav" units="liter"/>
<variable name="V_cyt" units="liter"/>
<variable initial_value="38e-12" name="V_cell" units="liter"/>
<variable initial_value="7.5e-15" name="J_cav_ecav" units="liters_per_second"/>
<variable initial_value="7.5e-14" name="J_cav_cyt" units="liters_per_second"/>
<variable initial_value="1.5e-17" name="J_ecav_cyt" units="liters_per_second"/>
<variable name="dcAMP_AC_56_dt" public_interface="in" units="uM_per_sec"/>
<variable name="dcAMP_AC_47_ecav_dt" public_interface="in" units="uM_per_sec"/>
<variable name="dcAMP_AC_47_cyt_dt" public_interface="in" units="uM_per_sec"/>
<variable name="dcAMP_cav_PDE2_dt" public_interface="in" units="uM_per_sec"/>
<variable name="dcAMP_cav_PDE3_dt" public_interface="in" units="uM_per_sec"/>
<variable name="dcAMP_cav_PDE4_dt" public_interface="in" units="uM_per_sec"/>
<variable name="dcAMP_ecav_PDE2_dt" public_interface="in" units="uM_per_sec"/>
<variable name="dcAMP_ecav_PDE4_dt" public_interface="in" units="uM_per_sec"/>
<variable name="dcAMP_cyt_PDE2_dt" public_interface="in" units="uM_per_sec"/>
<variable name="dcAMP_cyt_PDE3_dt" public_interface="in" units="uM_per_sec"/>
<variable name="dcAMP_cyt_PDE4_dt" public_interface="in" units="uM_per_sec"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>V_cav</ci>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.01</cn>
<ci>V_cell</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>V_ecav</ci>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.02</cn>
<ci>V_cell</ci>
</apply>
</apply>
<apply>
<eq/>
<ci>V_cyt</ci>
<apply>
<times/>
<cn xmlns:cellml="http://www.cellml.org/cellml/1.0#" cellml:units="dimensionless">0.5</cn>
<ci>V_cell</ci>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>cAMP_cav</ci>
</apply>
<apply>
<minus/>
<apply>
<minus/>
<apply>
<minus/>
<ci>dcAMP_AC_56_dt</ci>
<apply>
<plus/>
<ci>dcAMP_cav_PDE2_dt</ci>
<ci>dcAMP_cav_PDE3_dt</ci>
<ci>dcAMP_cav_PDE4_dt</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>J_cav_ecav</ci>
<apply>
<minus/>
<ci>cAMP_cav</ci>
<ci>cAMP_ecav</ci>
</apply>
</apply>
<ci>V_cav</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>J_cav_cyt</ci>
<apply>
<minus/>
<ci>cAMP_cav</ci>
<ci>cAMP_cyt</ci>
</apply>
</apply>
<ci>V_cav</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>cAMP_ecav</ci>
</apply>
<apply>
<minus/>
<apply>
<plus/>
<apply>
<minus/>
<ci>dcAMP_AC_47_ecav_dt</ci>
<apply>
<plus/>
<ci>dcAMP_ecav_PDE2_dt</ci>
<ci>dcAMP_ecav_PDE4_dt</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>J_cav_ecav</ci>
<apply>
<minus/>
<ci>cAMP_cav</ci>
<ci>cAMP_ecav</ci>
</apply>
</apply>
<ci>V_ecav</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>J_ecav_cyt</ci>
<apply>
<minus/>
<ci>cAMP_ecav</ci>
<ci>cAMP_cyt</ci>
</apply>
</apply>
<ci>V_ecav</ci>
</apply>
</apply>
</apply>
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>cAMP_cyt</ci>
</apply>
<apply>
<plus/>
<apply>
<minus/>
<ci>dcAMP_AC_47_cyt_dt</ci>
<apply>
<plus/>
<ci>dcAMP_cyt_PDE2_dt</ci>
<ci>dcAMP_cyt_PDE3_dt</ci>
<ci>dcAMP_cyt_PDE4_dt</ci>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>J_cav_cyt</ci>
<apply>
<minus/>
<ci>cAMP_cav</ci>
<ci>cAMP_cyt</ci>
</apply>
</apply>
<ci>V_cyt</ci>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>J_ecav_cyt</ci>
<apply>
<minus/>
<ci>cAMP_ecav</ci>
<ci>cAMP_cyt</ci>
</apply>
</apply>
<ci>V_cyt</ci>
</apply>
</apply>
</apply>
</math>
</component>
<connection>
<map_components component_1="environment" component_2="beta_1_adrenergic_parameters"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="muscarinic_parameters"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="caveolar_G_s_protein_activation_module"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="caveolar_G_i_protein_activation_module"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="extracaveolar_G_s_protein_activation_module"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="extracaveolar_G_i_protein_activation_module"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="environment" component_2="cAMP_flux_module"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection>
<map_components component_1="beta_1_adrenergic_parameters" component_2="caveolar_beta_1_adrenergic_receptor_module"/>
<map_variables variable_1="L_iso" variable_2="L_iso"/>
<map_variables variable_1="K_H" variable_2="K_H"/>
<map_variables variable_1="K_L" variable_2="K_L"/>
<map_variables variable_1="K_C" variable_2="K_C"/>
</connection>
<connection>
<map_components component_1="muscarinic_parameters" component_2="caveolar_muscarinic_receptor_module"/>
<map_variables variable_1="L_ach" variable_2="L_ach"/>
<map_variables variable_1="K_H" variable_2="K_H"/>
<map_variables variable_1="K_L" variable_2="K_L"/>
<map_variables variable_1="K_C" variable_2="K_C"/>
</connection>
<connection>
<map_components component_1="beta_1_adrenergic_parameters" component_2="extracaveolar_beta_1_adrenergic_receptor_module"/>
<map_variables variable_1="L_iso" variable_2="L_iso"/>
<map_variables variable_1="K_H" variable_2="K_H"/>
<map_variables variable_1="K_L" variable_2="K_L"/>
<map_variables variable_1="K_C" variable_2="K_C"/>
</connection>
<connection>
<map_components component_1="muscarinic_parameters" component_2="extracaveolar_muscarinic_receptor_module"/>
<map_variables variable_1="L_ach" variable_2="L_ach"/>
<map_variables variable_1="K_H" variable_2="K_H"/>
<map_variables variable_1="K_L" variable_2="K_L"/>
<map_variables variable_1="K_C" variable_2="K_C"/>
</connection>
<connection>
<map_components component_1="caveolar_G_s_protein_activation_module" component_2="AC56_module"/>
<map_variables variable_1="Gs_alpha_GTP" variable_2="Gs_alpha_GTP"/>
</connection>
<connection>
<map_components component_1="caveolar_G_i_protein_activation_module" component_2="AC56_module"/>
<map_variables variable_1="Gi_alpha_GTP" variable_2="Gi_alpha_GTP"/>
</connection>
<connection>
<map_components component_1="extracaveolar_G_s_protein_activation_module" component_2="AC47_ecav_module"/>
<map_variables variable_1="Gs_alpha_GTP" variable_2="Gs_alpha_GTP"/>
</connection>
<connection>
<map_components component_1="extracaveolar_G_i_protein_activation_module" component_2="AC47_ecav_module"/>
<map_variables variable_1="Gi_beta_gamma" variable_2="Gi_beta_gamma"/>
</connection>
<connection>
<map_components component_1="PDE_parameters" component_2="caveolar_PDE_module"/>
<map_variables variable_1="k_PDE2" variable_2="k_PDE2"/>
<map_variables variable_1="Km_PDE2" variable_2="Km_PDE2"/>
<map_variables variable_1="k_PDE3" variable_2="k_PDE3"/>
<map_variables variable_1="Km_PDE3" variable_2="Km_PDE3"/>
<map_variables variable_1="k_PDE4" variable_2="k_PDE4"/>
<map_variables variable_1="Km_PDE4" variable_2="Km_PDE4"/>
</connection>
<connection>
<map_components component_1="PDE_parameters" component_2="extracaveolar_PDE_module"/>
<map_variables variable_1="k_PDE2" variable_2="k_PDE2"/>
<map_variables variable_1="Km_PDE2" variable_2="Km_PDE2"/>
<map_variables variable_1="k_PDE4" variable_2="k_PDE4"/>
<map_variables variable_1="Km_PDE4" variable_2="Km_PDE4"/>
</connection>
<connection>
<map_components component_1="PDE_parameters" component_2="bulk_cytoplasmic_PDE_module"/>
<map_variables variable_1="k_PDE2" variable_2="k_PDE2"/>
<map_variables variable_1="Km_PDE2" variable_2="Km_PDE2"/>
<map_variables variable_1="k_PDE3" variable_2="k_PDE3"/>
<map_variables variable_1="Km_PDE3" variable_2="Km_PDE3"/>
<map_variables variable_1="k_PDE4" variable_2="k_PDE4"/>
<map_variables variable_1="Km_PDE4" variable_2="Km_PDE4"/>
</connection>
<connection>
<map_components component_1="G_s_parameters" component_2="caveolar_G_s_protein_activation_module"/>
<map_variables variable_1="k_act1" variable_2="k_act1"/>
<map_variables variable_1="k_act2" variable_2="k_act2"/>
<map_variables variable_1="k_hydr" variable_2="k_hydr"/>
<map_variables variable_1="k_reas" variable_2="k_reas"/>
</connection>
<connection>
<map_components component_1="G_i_parameters" component_2="caveolar_G_i_protein_activation_module"/>
<map_variables variable_1="k_act1" variable_2="k_act1"/>
<map_variables variable_1="k_act2" variable_2="k_act2"/>
<map_variables variable_1="k_hydr" variable_2="k_hydr"/>
<map_variables variable_1="k_reas" variable_2="k_reas"/>
</connection>
<connection>
<map_components component_1="G_s_parameters" component_2="extracaveolar_G_s_protein_activation_module"/>
<map_variables variable_1="k_act1" variable_2="k_act1"/>
<map_variables variable_1="k_act2" variable_2="k_act2"/>
<map_variables variable_1="k_hydr" variable_2="k_hydr"/>
<map_variables variable_1="k_reas" variable_2="k_reas"/>
</connection>
<connection>
<map_components component_1="G_i_parameters" component_2="extracaveolar_G_i_protein_activation_module"/>
<map_variables variable_1="k_act1" variable_2="k_act1"/>
<map_variables variable_1="k_act2" variable_2="k_act2"/>
<map_variables variable_1="k_hydr" variable_2="k_hydr"/>
<map_variables variable_1="k_reas" variable_2="k_reas"/>
</connection>
<connection>
<map_components component_1="caveolar_beta_1_adrenergic_receptor_module" component_2="caveolar_G_s_protein_activation_module"/>
<map_variables variable_1="G" variable_2="Gs_alpha_beta_gamma"/>
<map_variables variable_1="RG" variable_2="RG"/>
<map_variables variable_1="LRG" variable_2="LRG"/>
</connection>
<connection>
<map_components component_1="caveolar_muscarinic_receptor_module" component_2="caveolar_G_i_protein_activation_module"/>
<map_variables variable_1="G" variable_2="Gi_alpha_beta_gamma"/>
<map_variables variable_1="RG" variable_2="RG"/>
<map_variables variable_1="LRG" variable_2="LRG"/>
</connection>
<connection>
<map_components component_1="extracaveolar_beta_1_adrenergic_receptor_module" component_2="extracaveolar_G_s_protein_activation_module"/>
<map_variables variable_1="G" variable_2="Gs_alpha_beta_gamma"/>
<map_variables variable_1="RG" variable_2="RG"/>
<map_variables variable_1="LRG" variable_2="LRG"/>
</connection>
<connection>
<map_components component_1="extracaveolar_muscarinic_receptor_module" component_2="extracaveolar_G_i_protein_activation_module"/>
<map_variables variable_1="G" variable_2="Gi_alpha_beta_gamma"/>
<map_variables variable_1="RG" variable_2="RG"/>
<map_variables variable_1="LRG" variable_2="LRG"/>
</connection>
<connection>
<map_components component_1="AC56_module" component_2="cAMP_flux_module"/>
<map_variables variable_1="dcAMP_AC_56_dt" variable_2="dcAMP_AC_56_dt"/>
</connection>
<connection>
<map_components component_1="AC47_ecav_module" component_2="cAMP_flux_module"/>
<map_variables variable_1="dcAMP_AC_47_ecav_dt" variable_2="dcAMP_AC_47_ecav_dt"/>
</connection>
<connection>
<map_components component_1="AC47_cyt_module" component_2="cAMP_flux_module"/>
<map_variables variable_1="dcAMP_AC_47_cyt_dt" variable_2="dcAMP_AC_47_cyt_dt"/>
</connection>
<connection>
<map_components component_1="caveolar_PDE_module" component_2="cAMP_flux_module"/>
<map_variables variable_1="dcAMP_cav_PDE2_dt" variable_2="dcAMP_cav_PDE2_dt"/>
<map_variables variable_1="dcAMP_cav_PDE3_dt" variable_2="dcAMP_cav_PDE3_dt"/>
<map_variables variable_1="dcAMP_cav_PDE4_dt" variable_2="dcAMP_cav_PDE4_dt"/>
<map_variables variable_1="cAMP_cav" variable_2="cAMP_cav"/>
</connection>
<connection>
<map_components component_1="extracaveolar_PDE_module" component_2="cAMP_flux_module"/>
<map_variables variable_1="dcAMP_ecav_PDE2_dt" variable_2="dcAMP_ecav_PDE2_dt"/>
<map_variables variable_1="dcAMP_ecav_PDE4_dt" variable_2="dcAMP_ecav_PDE4_dt"/>
<map_variables variable_1="cAMP_ecav" variable_2="cAMP_ecav"/>
</connection>
<connection>
<map_components component_1="bulk_cytoplasmic_PDE_module" component_2="cAMP_flux_module"/>
<map_variables variable_1="dcAMP_cyt_PDE2_dt" variable_2="dcAMP_cyt_PDE2_dt"/>
<map_variables variable_1="dcAMP_cyt_PDE3_dt" variable_2="dcAMP_cyt_PDE3_dt"/>
<map_variables variable_1="dcAMP_cyt_PDE4_dt" variable_2="dcAMP_cyt_PDE4_dt"/>
<map_variables variable_1="cAMP_cyt" variable_2="cAMP_cyt"/>
</connection>
<rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#">
<foo xmlns="http://www.example.org/foo/bar/baz"/>
- <!--
The following RDF block contains metadata that applies to this document
as a whole, as indicated by the empty about attribute on the
<rdf:Description> element.
-->
- <rdf:Description rdf:about="">
- <!--
The Model Builder Metadata. The Dublin Core "creator" element is used
to indicate the person who translated the model into CellML.
-->
- <dc:creator xmlns:dc="http://purl.org/dc/elements/1.1/" rdf:parseType="Resource">
- <vCard:N xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" rdf:parseType="Resource">
<vCard:Family>Nunns</vCard:Family>
<vCard:Given>Geoffrey</vCard:Given>
<vCard:Other>Rogan</vCard:Other>
</vCard:N>
- <vCard:EMAIL xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" rdf:parseType="Resource">
<rdf:value>gnunns1@jhu.edu</rdf:value>
<rdf:type rdf:resource="http://imc.org/vCard/3.0#internet"/>
</vCard:EMAIL>
- <vCard:ORG xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" rdf:parseType="Resource">
<vCard:Orgname>The University of Auckland</vCard:Orgname>
<vCard:Orgunit>Auckland Bioengineering Institute</vCard:Orgunit>
</vCard:ORG>
</dc:creator>
- <!--
The Creation Date metadata. This is the date on which the model
was translated into CellML.
-->
- <dcterms:created xmlns:dcterms="http://purl.org/dc/terms/" rdf:parseType="Resource">
<dcterms:W3CDTF>2009-10-08</dcterms:W3CDTF>
</dcterms:created>
- <!--
The Modification History metadata. This lists the changes that have been
made to the document, who made the changes, and when they were made.
-->
</rdf:Description>
- <!--
The following metadata refers to the model itself, as indicated by the
reference to the ID "aslanidi_2009", which is
declared on the <model> element.
-->
- <rdf:Description rdf:about="#iancu_jones_harvey_2007">
- <!-- A human readable name for the model.
-->
<dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">The Iancu et al. 2007 model of compartmentalized cAMP signaling in cardiac myocytes</dc:title>
- <!-- A comment regarding the model.
-->
- <cmeta:comment rdf:parseType="Resource">
<rdf:value>This is the CellML description of Iancu et al.'s mathematical model of compartmentalized cAMP signaling in cardiac myocytes</rdf:value>
- <!-- The creator of the comment.
-->
- <dc:creator xmlns:dc="http://purl.org/dc/elements/1.1/" rdf:parseType="Resource">
<vCard:FN xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">Geoffrey Nunns</vCard:FN>
</dc:creator>
</cmeta:comment>
<cmeta:species>Human</cmeta:species>
<cmeta:bio_entity>ventricular myocyte</cmeta:bio_entity>
- <!-- Keyword(s)
-->
- <bqs:reference xmlns:bqs="http://www.cellml.org/bqs/1.0#" rdf:parseType="Resource">
- <dc:subject xmlns:dc="http://purl.org/dc/elements/1.1/" rdf:parseType="Resource">
<bqs:subject_type>keyword</bqs:subject_type>
- <rdf:value>
- <rdf:Bag>
<rdf:li>signal transduction</rdf:li>
<rdf:li>cardiac</rdf:li>
</rdf:Bag>
</rdf:value>
</dc:subject>
</bqs:reference>
- <bqs:reference xmlns:bqs="http://www.cellml.org/bqs/1.0#" rdf:parseType="Resource">
<bqs:Pubmed_id>17293406</bqs:Pubmed_id>
- <bqs:JournalArticle rdf:parseType="Resource">
- <dc:creator xmlns:dc="http://purl.org/dc/elements/1.1/">
- <rdf:Seq>
- <rdf:li rdf:parseType="Resource">
- <bqs:Person rdf:parseType="Resource">
- <vCard:N xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" rdf:parseType="Resource">
<vCard:Family>Iancu</vCard:Family>
<vCard:Given>Radu</vCard:Given>
<vCard:Other>V</vCard:Other>
</vCard:N>
</bqs:Person>
</rdf:li>
- <rdf:li rdf:parseType="Resource">
- <bqs:Person rdf:parseType="Resource">
- <vCard:N xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" rdf:parseType="Resource">
<vCard:Family>Jones</vCard:Family>
<vCard:Given>Stephen</vCard:Given>
<vCard:Other>W</vCard:Other>
</vCard:N>
</bqs:Person>
</rdf:li>
- <rdf:li rdf:parseType="Resource">
- <bqs:Person rdf:parseType="Resource">
- <vCard:N xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" rdf:parseType="Resource">
<vCard:Family>Harvey</vCard:Family>
<vCard:Given>Robert</vCard:Given>
<vCard:Other>D</vCard:Other>
</vCard:N>
</bqs:Person>
</rdf:li>
-
</rdf:Seq>
</dc:creator>
<dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Compartmentation of cAMP signaling in cardiac myocytes: a computational study</dc:title>
- <dcterms:issued xmlns:dcterms="http://purl.org/dc/terms/" rdf:parseType="Resource">
<dcterms:W3CDTF>2007-05-01</dcterms:W3CDTF>
</dcterms:issued>
- <bqs:Journal rdf:parseType="Resource">
<dc:title xmlns:dc="http://purl.org/dc/elements/1.1/">Biophysical Journal</dc:title>
</bqs:Journal>
<bqs:volume>92</bqs:volume>
<bqs:first_page>3317</bqs:first_page>
<bqs:last_page>3331</bqs:last_page>
</bqs:JournalArticle>
</bqs:reference>
</rdf:Description>
</rdf:RDF>
</model>
