<?xml version="1.0" encoding="utf-8"?>
<!--
This CellML file was generated on 14/05/2010 at 11:00:54 at a.m. using:
COR (0.9.31.1371)
Copyright 2002-2010 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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<title>A Mathematical Model Of Cardiocyte Ca2+ Dynamics</title>
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<firstname>Catherine</firstname>
<surname>Lloyd</surname>
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<shortaffil>Auckland Bioengineering Institute, The University of Auckland</shortaffil>
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<section id="sec_status">
<title>Model Status</title>
<para>
This model runs in OpenCell and COR and the units are consistent throughout. It does not at present replicate the published results, most likely because there are a number of gating or switching processes described in the paper that were unable to be replicated precisely.
</para>
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<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
ABSTRACT: Cardiac contraction and relaxation dynamics result from a set of simultaneously interacting Ca(2+) regulatory mechanisms. In this study, cardiocyte Ca(2+) dynamics were modeled using a set of six differential equations that were based on theories, equations, and parameters described in previous studies. Among the unique features of the model was the inclusion of bidirectional modulatory interplay between the sarcoplasmic reticular Ca(2+) release channel (SRRC) and calsequestrin (CSQ) in the SR lumen, where CSQ acted as a dynamic rather than simple Ca(2+) buffer, and acted as a Ca(2+) sensor in the SR lumen as well. The inclusion of this control mechanism was central in overcoming a number of assumptions that would otherwise have to be made about SRRC kinetics, SR Ca(2+) release rates, and SR Ca(2+) release termination when the SR lumen is assumed to act as a simple, buffered Ca(2+) sink. The model was sufficient to reproduce a graded Ca(2+)-induced Ca(2+) release (CICR) response, CICR with high gain, and a system with reasonable stability. As constructed, the model successfully replicated the results of several previously published experiments that dealt with the Ca(2+) dependence of the SRRC (, J. Gen. Physiol. 85:247-289), the refractoriness of the SRRC (, Am. J. Physiol. 270:C148-C159), the SR Ca(2+) load dependence of SR Ca(2+) release (, Am. J. Physiol. 268:C1313-C1329;, J. Biol. Chem. 267:20850-20856), SR Ca(2+) leak (, J. Physiol. (Lond.). 474:463-471;, Biophys. J. 68:2015-2022), SR Ca(2+) load regulation by leak and uptake (, J. Gen. Physiol. 111:491-504), the effect of Ca(2+) trigger duration on SR Ca(2+) release (, Am. J. Physiol. 258:C944-C954), the apparent relationship that exists between sarcoplasmic and sarcoplasmic reticular calcium concentrations (, Biophys. J. 73:1524-1531), and a variety of contraction frequency-dependent alterations in sarcoplasmic [Ca(2+)] dynamics that are normally observed in the laboratory, including rest potentiation, a negative frequency-[Ca(2+)] relationship, and extrasystolic potentiation. Furthermore, under the condition of a simulated Ca(2+) overload, an alternans-like state was produced. In summary, the current model of cardiocyte Ca(2+) dynamics provides an integrated theoretical framework of fundamental cellular Ca(2+) regulatory processes that is sufficient to predict a broad array of observable experimental outcomes.
</para>
<para>
The original paper reference is cited below:
</para>
<para>
A Mathematical Model of Cardiocyte Ca<superscript>2+</superscript> Dynamics with a Novel Representation of Sarcoplasmic Reticular Ca<superscript>2+</superscript> Control, Steven M. Snyder, Bradley M. Palmer and Russell L. Moore, 2000, <emphasis>Biophysical Journal</emphasis>, 79, 94-115. <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10866940&dopt=Abstract">PubMed ID: 10866940</ulink>
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<title>cell schematic for the model</title>
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<caption>Cell schematic for the model representing three intracellular compartments with buffering, the extracellular space, and the related Ca<superscript>2+</superscript> movement processes.</caption>
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</sect1>
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<variable name="Ca_s" units="molar" public_interface="in"/>
<variable name="Km_s" units="molar" initial_value="0.00000025"/>
<variable name="Vmax_s" units="flux" initial_value="0.000525"/>
<variable name="Rate_Ca_uptake_by_SR_Ca_ATPase" units="flux" public_interface="out"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>Rate_Ca_uptake_by_SR_Ca_ATPase</ci>
<apply>
<divide/>
<apply>
<times/>
<ci>Vmax_s</ci>
<apply>
<minus/>
<apply>
<power/>
<ci>Ca_c</ci>
<cn cellml:units="dimensionless">2</cn>
</apply>
<apply>
<divide/>
<apply>
<power/>
<ci>Ca_s</ci>
<cn cellml:units="dimensionless">2</cn>
</apply>
<apply>
<power/>
<cn cellml:units="dimensionless">7000</cn>
<cn cellml:units="dimensionless">2</cn>
</apply>
</apply>
</apply>
</apply>
<apply>
<plus/>
<apply>
<power/>
<ci>Km_s</ci>
<cn cellml:units="dimensionless">2</cn>
</apply>
<apply>
<power/>
<ci>Ca_c</ci>
<cn cellml:units="dimensionless">2</cn>
</apply>
<apply>
<divide/>
<apply>
<power/>
<ci>Ca_s</ci>
<cn cellml:units="dimensionless">2</cn>
</apply>
<apply>
<power/>
<cn cellml:units="dimensionless">7000</cn>
<cn cellml:units="dimensionless">2</cn>
</apply>
</apply>
</apply>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="Ca_buffering_in_the_SR">
<variable name="Ca_CSQ" units="molar" public_interface="in"/>
<variable name="Ca_s" units="molar" public_interface="in"/>
<variable name="K_ons" units="second_order_rate_constant" initial_value="8772"/>
<variable name="K_offs" units="first_order_rate_constant" initial_value="5.596536"/>
<variable name="Bmax_s" units="molar" initial_value="0.008"/>
<variable name="Rate_Ca_buffering_in_the_SR" units="flux" public_interface="out"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<ci>Rate_Ca_buffering_in_the_SR</ci>
<apply>
<minus/>
<apply>
<times/>
<ci>K_ons</ci>
<ci>Ca_s</ci>
<apply>
<minus/>
<ci>Bmax_s</ci>
<ci>Ca_CSQ</ci>
</apply>
</apply>
<apply>
<times/>
<ci>K_offs</ci>
<ci>Ca_CSQ</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="fuzzy_space_calcium">
<variable name="Ca_f" units="molar" initial_value="0.12e-6" public_interface="out"/>
<variable name="Rt" units="molar" initial_value="0.00000015"/>
<variable name="Bmax_f1" units="molar" initial_value="0.0002"/>
<variable name="Bmax_f2" units="molar" initial_value="0.0011"/>
<variable name="Kb_f1" units="molar" initial_value="0.000017"/>
<variable name="Kb_f2" units="molar" initial_value="0.000013"/>
<variable name="V_f" units="dimensionless" initial_value="0.0013"/>
<variable name="Rate_Ca_influx_across_the_SR" units="flux" public_interface="in"/>
<variable name="Rate_Ca_movement_through_the_SRRC" units="flux" public_interface="in"/>
<variable name="Rate_Ca_efflux_across_the_SR_by_NaCa_exchange" units="flux" public_interface="in"/>
<variable name="Rate_Ca_movement_between_the_fuzzy_space_and_cytosol" units="flux" public_interface="in"/>
<variable name="dcas1_dt" units="first_order_rate_constant" public_interface="in"/>
<variable name="dcas2_dt" units="first_order_rate_constant" public_interface="in"/>
<variable name="time" units="second" public_interface="in"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Ca_f</ci>
</apply>
<apply>
<divide/>
<apply>
<plus/>
<apply>
<minus/>
<ci>Rate_Ca_movement_through_the_SRRC</ci>
<apply>
<plus/>
<apply>
<times/>
<ci>Rt</ci>
<apply>
<plus/>
<ci>dcas1_dt</ci>
<ci>dcas2_dt</ci>
</apply>
</apply>
<ci>Rate_Ca_movement_between_the_fuzzy_space_and_cytosol</ci>
<ci>Rate_Ca_efflux_across_the_SR_by_NaCa_exchange</ci>
</apply>
</apply>
<ci>Rate_Ca_influx_across_the_SR</ci>
</apply>
<apply>
<plus/>
<apply>
<divide/>
<apply>
<times/>
<ci>Bmax_f1</ci>
<ci>Kb_f1</ci>
</apply>
<apply>
<power/>
<apply>
<plus/>
<ci>Ca_f</ci>
<ci>Kb_f1</ci>
</apply>
<cn cellml:units="dimensionless">2</cn>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>Bmax_f2</ci>
<ci>Kb_f2</ci>
</apply>
<apply>
<power/>
<apply>
<plus/>
<ci>Ca_f</ci>
<ci>Kb_f2</ci>
</apply>
<cn cellml:units="dimensionless">2</cn>
</apply>
</apply>
<ci>V_f</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="cytosolic_calcium">
<variable name="Ca_c" units="molar" initial_value="1e-7" public_interface="out"/>
<variable name="Bmax_c" units="molar" initial_value="0.00012"/>
<variable name="dye_c" units="molar" initial_value="0"/>
<variable name="Kb_c" units="molar" initial_value="0.00000096"/>
<variable name="Kb_dye" units="molar" initial_value="2e-7"/>
<variable name="V_c" units="dimensionless" initial_value="0.9287"/>
<variable name="Rate_Ca_movement_between_the_fuzzy_space_and_cytosol" units="flux" public_interface="in"/>
<variable name="Rate_Ca_uptake_by_SR_Ca_ATPase" units="flux" public_interface="in"/>
<variable name="time" units="second" public_interface="in"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Ca_c</ci>
</apply>
<apply>
<divide/>
<apply>
<minus/>
<ci>Rate_Ca_movement_between_the_fuzzy_space_and_cytosol</ci>
<ci>Rate_Ca_uptake_by_SR_Ca_ATPase</ci>
</apply>
<apply>
<plus/>
<apply>
<divide/>
<apply>
<times/>
<ci>Bmax_c</ci>
<ci>Kb_c</ci>
</apply>
<apply>
<power/>
<apply>
<plus/>
<ci>Ca_c</ci>
<ci>Kb_c</ci>
</apply>
<cn cellml:units="dimensionless">2</cn>
</apply>
</apply>
<apply>
<divide/>
<apply>
<times/>
<ci>dye_c</ci>
<ci>Kb_dye</ci>
</apply>
<apply>
<power/>
<apply>
<plus/>
<ci>Ca_c</ci>
<ci>Kb_dye</ci>
</apply>
<cn cellml:units="dimensionless">2</cn>
</apply>
</apply>
<ci>V_c</ci>
</apply>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="SR_calcium">
<variable name="Ca_s" units="molar" initial_value="201e-6" public_interface="out"/>
<variable name="V_s" units="dimensionless" initial_value="0.07"/>
<variable name="Rate_Ca_movement_through_the_SRRC" units="flux" public_interface="in"/>
<variable name="Rate_Ca_uptake_by_SR_Ca_ATPase" units="flux" public_interface="in"/>
<variable name="Rate_Ca_buffering_in_the_SR" units="flux" public_interface="in"/>
<variable name="time" units="second" public_interface="in"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Ca_s</ci>
</apply>
<apply>
<minus/>
<apply>
<divide/>
<apply>
<minus/>
<ci>Rate_Ca_uptake_by_SR_Ca_ATPase</ci>
<ci>Rate_Ca_movement_through_the_SRRC</ci>
</apply>
<ci>V_s</ci>
</apply>
<ci>Rate_Ca_buffering_in_the_SR</ci>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="extracellular_calcium">
<variable name="Ca_e" units="molar" initial_value="0.002" public_interface="out"/>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="calsequestrin_bound_calcium">
<variable name="Ca_CSQ" units="molar" initial_value="0" public_interface="out"/>
<variable name="time" units="second" public_interface="in"/>
<variable name="Rate_Ca_buffering_in_the_SR" units="flux" public_interface="in"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Ca_CSQ</ci>
</apply>
<ci>Rate_Ca_buffering_in_the_SR</ci>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="SRRC_fast_activating_binding_site">
<variable name="S1" units="molar" initial_value="0" public_interface="out"/>
<variable name="dCa2_S1_dt" units="flux" public_interface="in"/>
<variable name="time" units="second" public_interface="in"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>S1</ci>
</apply>
<apply>
<minus/>
<ci>dCa2_S1_dt</ci>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="SRRC_slow_inactivating_binding_site">
<variable name="S2" units="molar" initial_value="0" public_interface="out"/>
<variable name="dCa_S2_dt" units="flux" public_interface="in"/>
<variable name="time" units="second" public_interface="in"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>S2</ci>
</apply>
<apply>
<minus/>
<ci>dCa_S2_dt</ci>
</apply>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="Ca_bound_to_the_SRRC_fast_activating_binding_site">
<variable name="Ca_2_S1" units="molar" initial_value="0" public_interface="out"/>
<variable name="dCa2_S1_dt" units="flux" public_interface="in"/>
<variable name="time" units="second" public_interface="in"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Ca_2_S1</ci>
</apply>
<ci>dCa2_S1_dt</ci>
</apply>
</math>
</component>
<component xmlns="http://www.cellml.org/cellml/1.0#" name="Ca_bound_to_the_SRRC_slow_inactivating_binding_site">
<variable name="Ca_S2" units="molar" initial_value="0" public_interface="out"/>
<variable name="dCa_S2_dt" units="flux" public_interface="in"/>
<variable name="time" units="second" public_interface="in"/>
<math xmlns="http://www.w3.org/1998/Math/MathML">
<apply>
<eq/>
<apply>
<diff/>
<bvar>
<ci>time</ci>
</bvar>
<ci>Ca_S2</ci>
</apply>
<ci>dCa_S2_dt</ci>
</apply>
</math>
</component>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_influx_across_the_SR" component_2="extracellular_calcium"/>
<map_variables variable_1="Ca_e" variable_2="Ca_e"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_influx_across_the_SR" component_2="fuzzy_space_calcium"/>
<map_variables variable_1="Ca_f" variable_2="Ca_f"/>
<map_variables variable_1="Rate_Ca_influx_across_the_SR" variable_2="Rate_Ca_influx_across_the_SR"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_movement_through_the_SRRC" component_2="Ca_bound_to_the_SRRC_fast_activating_binding_site"/>
<map_variables variable_1="dCa2_S1_dt" variable_2="dCa2_S1_dt"/>
<map_variables variable_1="Ca_2_S1" variable_2="Ca_2_S1"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_movement_through_the_SRRC" component_2="Ca_bound_to_the_SRRC_slow_inactivating_binding_site"/>
<map_variables variable_1="dCa_S2_dt" variable_2="dCa_S2_dt"/>
<map_variables variable_1="Ca_S2" variable_2="Ca_S2"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_movement_through_the_SRRC" component_2="SRRC_fast_activating_binding_site"/>
<map_variables variable_1="dCa2_S1_dt" variable_2="dCa2_S1_dt"/>
<map_variables variable_1="S1" variable_2="S1"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_movement_through_the_SRRC" component_2="SRRC_slow_inactivating_binding_site"/>
<map_variables variable_1="dCa_S2_dt" variable_2="dCa_S2_dt"/>
<map_variables variable_1="S2" variable_2="S2"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_movement_through_the_SRRC" component_2="fuzzy_space_calcium"/>
<map_variables variable_1="Ca_f" variable_2="Ca_f"/>
<map_variables variable_1="dcas1_dt" variable_2="dcas1_dt"/>
<map_variables variable_1="dcas2_dt" variable_2="dcas2_dt"/>
<map_variables variable_1="Rate_Ca_movement_through_the_SRRC" variable_2="Rate_Ca_movement_through_the_SRRC"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_movement_through_the_SRRC" component_2="SR_calcium"/>
<map_variables variable_1="Ca_s" variable_2="Ca_s"/>
<map_variables variable_1="Rate_Ca_movement_through_the_SRRC" variable_2="Rate_Ca_movement_through_the_SRRC"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_efflux_across_the_SR_by_NaCa_exchange" component_2="fuzzy_space_calcium"/>
<map_variables variable_1="Ca_f" variable_2="Ca_f"/>
<map_variables variable_1="Rate_Ca_efflux_across_the_SR_by_NaCa_exchange" variable_2="Rate_Ca_efflux_across_the_SR_by_NaCa_exchange"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_movement_between_the_fuzzy_space_and_cytosol" component_2="fuzzy_space_calcium"/>
<map_variables variable_1="Ca_f" variable_2="Ca_f"/>
<map_variables variable_1="Rate_Ca_movement_between_the_fuzzy_space_and_cytosol" variable_2="Rate_Ca_movement_between_the_fuzzy_space_and_cytosol"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_movement_between_the_fuzzy_space_and_cytosol" component_2="cytosolic_calcium"/>
<map_variables variable_1="Ca_c" variable_2="Ca_c"/>
<map_variables variable_1="Rate_Ca_movement_between_the_fuzzy_space_and_cytosol" variable_2="Rate_Ca_movement_between_the_fuzzy_space_and_cytosol"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_uptake_by_SR_Ca_ATPase" component_2="cytosolic_calcium"/>
<map_variables variable_1="Ca_c" variable_2="Ca_c"/>
<map_variables variable_1="Rate_Ca_uptake_by_SR_Ca_ATPase" variable_2="Rate_Ca_uptake_by_SR_Ca_ATPase"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_uptake_by_SR_Ca_ATPase" component_2="SR_calcium"/>
<map_variables variable_1="Ca_s" variable_2="Ca_s"/>
<map_variables variable_1="Rate_Ca_uptake_by_SR_Ca_ATPase" variable_2="Rate_Ca_uptake_by_SR_Ca_ATPase"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_buffering_in_the_SR" component_2="SR_calcium"/>
<map_variables variable_1="Ca_s" variable_2="Ca_s"/>
<map_variables variable_1="Rate_Ca_buffering_in_the_SR" variable_2="Rate_Ca_buffering_in_the_SR"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_buffering_in_the_SR" component_2="calsequestrin_bound_calcium"/>
<map_variables variable_1="Ca_CSQ" variable_2="Ca_CSQ"/>
<map_variables variable_1="Rate_Ca_buffering_in_the_SR" variable_2="Rate_Ca_buffering_in_the_SR"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_movement_through_the_SRRC" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="fuzzy_space_calcium" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="cytosolic_calcium" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="SR_calcium" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="calsequestrin_bound_calcium" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="SRRC_fast_activating_binding_site" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="SRRC_slow_inactivating_binding_site" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_bound_to_the_SRRC_fast_activating_binding_site" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
<connection xmlns="http://www.cellml.org/cellml/1.0#">
<map_components component_1="Ca_bound_to_the_SRRC_slow_inactivating_binding_site" component_2="environment"/>
<map_variables variable_1="time" variable_2="time"/>
</connection>
</model>