- Author:
- AnandR <a.rampadarath@auckland.ac.nz>
- Date:
- 2019-04-05 14:25:01+13:00
- Desc:
- Added some semgen annotated models (AnandR)
- Permanent Source URI:
- https://models.physiomeproject.org/workspace/584/rawfile/ade7933153a72bb89e0b02d75db92d6e4be285f5/De_Young_1992.cellml
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<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>IP3-Mediated Ca2+ Release</title>
<author>
<firstname>Catherine</firstname>
<surname>Lloyd</surname>
<affiliation>
<shortaffil>Bioengineering Institute, University of Auckland</shortaffil>
</affiliation>
</author>
</articleinfo>
<sect1 id="sec_structure">
<title>Model Structure</title>
<para>
Ca
<superscript>2+</superscript>
is a ubiquitous intracellular secondary messenger, and evidence from several different cell types suggests that an important mode of signalling is through oscillations rather than the maintenance of a steady state level. The oscillatory behaviour of inositol 1,4,5-triphosphate (IP3)-mediated Ca
<superscript>2+</superscript>
release has been modelled by Gary W. De Young and Joel Keizer. Their 1992 paper is referenced fully below.
</para>
<para>
<ulink url="http://www.pnas.org/cgi/content/abstract/89/20/9895">
A single-pool inositol 1,4,5-triphosphate-receptor-based model for agonist-stimulated oscillations in Ca
<superscript>2+</superscript>
concentration
</ulink>
, Gary W. De Young and Joel Keizer, 1992,
<ulink url="http://www.pnas.org/">
<emphasis>Proc. Natl. Acad. Sci. USA</emphasis>
</ulink>
, 89, 9895-9899. (A
<ulink url="http://www.pnas.org/cgi/reprint/89/20/9895.pdf">PDF</ulink>
of the article is available to subscribers on the PNAS website.)
<ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1329108&dopt=Abstract">PubMed ID: 1329108</ulink>
</para>
<para>
Several mechanisms have been proposed to explain oscillations of intracellular Ca
<superscript>2+</superscript>
concentration in cells. In this study, De Young and Keizer investigate the idea that a biphasic response of the IP3 receptor/channel to cytosolic Ca
<superscript>2+</superscript>
may alone be sufficient to induce Ca
<superscript>2+</superscript>
oscillations.
</para>
<para>
They constructed a simplified model of the IP3 receptor/channel by assuming that three equivalent and independent subunits are involved in Ca
<superscript>2+</superscript>
conduction. Each subunit has three binding sites: one for IP3, one for Ca
<superscript>2+</superscript>
activation, and one for Ca
<superscript>2+</superscript>
inactivation. Thus each subunit may exist in eight states with transitions governed by second-order (association) and first-order (dissociation) rate constants (see
<xref linkend="fig_pathway_diagram" />
below). All three subunits must be in the state S
<subscript>110</subscript>
(one IP3 and one activating Ca
<superscript>2+</superscript>
bound) for the channel to be open and conducting.
</para>
<para>
The raw CellML description of the IP3-mediated Ca
<superscript>2+</superscript>
release model can be downloaded in various formats as described in
<xref linkend="sec_download_this_model" />
.
</para>
<informalfigure float="0" id="fig_pathway_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>A schematic diagram of the kinetics of an IP3 receptor/channel subunit</title>
</objectinfo>
<imagedata fileref="deyoung_1992.png" />
</imageobject>
</mediaobject>
<caption>
A schematic diagram of the kinetics of an IP
<subscript>3</subscript>
receptor/channel subunit.
</caption>
</informalfigure>
</sect1>
</article>
</documentation>
<units name="micromolar">
<unit prefix="micro" units="mole" />
<unit exponent="-1.0" units="litre" />
</units>
<units name="flux">
<unit units="micromolar" />
<unit exponent="-1.0" units="second" />
</units>
<units name="first_order_rate_constant">
<unit exponent="-1.0" units="second" />
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<variable cmeta:id="constants.d3" name="d3" public_interface="in" units="nanomolar" />
<variable cmeta:id="constants.a1" name="a1" public_interface="out" units="second_order_rate_constant" />
<variable cmeta:id="constants.b2" name="b2" public_interface="out" units="first_order_rate_constant" />
<variable cmeta:id="constants.d4" name="d4" public_interface="in" units="nanomolar" />
<variable cmeta:id="constants.a2" name="a2" public_interface="out" units="second_order_rate_constant" />
<variable cmeta:id="constants.b3" name="b3" public_interface="out" units="first_order_rate_constant" />
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<eq />
<ci>b1</ci>
<apply>
<times />
<ci>d1</ci>
<ci>a1</ci>
</apply>
</apply>
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<eq />
<ci>b3</ci>
<apply>
<times />
<ci>d3</ci>
<ci>a3</ci>
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</apply>
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<eq />
<ci>b4</ci>
<apply>
<times />
<ci>d4</ci>
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</apply>
</apply>
</math>
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<connection>
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<connection>
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<connection>
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<connection>
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<connection>
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</connection>
<connection>
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<map_variables variable_1="d3" variable_2="d3" />
<map_variables variable_1="d5" variable_2="d5" />
<map_variables variable_1="d1" variable_2="d1" />
<map_variables variable_1="d2" variable_2="d2" />
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<connection>
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</connection>
<connection>
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<connection>
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<connection>
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<map_variables variable_1="b2" variable_2="b2" />
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<connection>
<map_components component_1="probability_of_an_open_IP3_receptor_channel" component_2="Ca_i" />
<map_variables variable_1="P_open" variable_2="P_open" />
</connection>
<connection>
<map_components component_1="Ca_ER" component_2="Ca_i" />
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<connection>
<map_components component_1="Ca_i" component_2="IP3" />
<map_variables variable_1="Ca_i" variable_2="Ca_i" />
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<connection>
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<map_variables variable_1="V3" variable_2="V3" />
<map_variables variable_1="V2" variable_2="V2" />
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<connection>
<map_components component_1="x_001" component_2="fluxes" />
<map_variables variable_1="x_001" variable_2="x_001" />
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<connection>
<map_components component_1="environment" component_2="x_010" />
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<connection>
<map_components component_1="x_011" component_2="fluxes" />
<map_variables variable_1="x_011" variable_2="x_011" />
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<connection>
<map_components component_1="receptor_dissociation_constants" component_2="fluxes" />
<map_variables variable_1="d4" variable_2="d4" />
<map_variables variable_1="d5" variable_2="d5" />
</connection>
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<rdf:Description rdf:about="#receptor_dissociation_constants.d1">
<dcterms:description>IP3 receptor dissociation constant</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#x_011.x_001">
<dcterms:description>Proportion of IP3 receptor subunits with Ca inactivation site bound.</dcterms:description>
</rdf:Description>
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<dcterms:description>IP3 receptor binding constant</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#receptor_dissociation_constants.a3">
<dcterms:description>IP3 receptor binding constant</dcterms:description>
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<rdf:Description rdf:about="#Ca_ER.time">
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<rdf:Description rdf:about="#fluxes.Ca_i">
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<dcterms:description>Cytosolic free Ca concentration</dcterms:description>
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<rdf:Description rdf:about="#fluxes.d5">
<dcterms:description>Ca receptor dissociation constant (activation)</dcterms:description>
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<dcterms:description>Ca receptor dissociation constant (inhibition)</dcterms:description>
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<dcterms:description>Cytosolic free Ca concentration</dcterms:description>
</rdf:Description>
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<dcterms:description>Time domain</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#x_011.x_000">
<dcterms:description>Proportion of IP3 receptor subunits with all receptors unbound.</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#fluxes.x_010">
<dcterms:description>Proportion of IP3 receptor subunits with Ca activation site bound.</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#receptor_dissociation_constants.a2">
<dcterms:description>Ca receptor binding constant (inhibition)</dcterms:description>
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<rdf:Description rdf:about="#x_000.x_000">
<dcterms:description>Proportion of IP3 receptor subunits with all receptors unbound.</dcterms:description>
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<rdf:Description rdf:about="#constants.a2">
<dcterms:description>Ca receptor binding constant (inhibition)</dcterms:description>
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<dcterms:description>Ca concentration in the endoplasmic reticulum.</dcterms:description>
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<rdf:Description rdf:about="#Ca_i.c1">
<dcterms:description>Volume ratio of endoplasmic reticulum and cytosol</dcterms:description>
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<dcterms:description>Cytosolic free Ca concentration</dcterms:description>
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<rdf:Description rdf:about="#probability_of_an_open_IP3_receptor_channel.d3">
<dcterms:description>IP3 receptor dissociation constant</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#fluxes.x_011">
<dcterms:description>Proportion of IP3 receptor subunits with Ca activation and deactivation sites bound.</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#x_011.x_011">
<dcterms:description>Proportion of IP3 receptor subunits with Ca activation and deactivation sites bound.</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#constants.a1">
<dcterms:description>IP3 receptor binding constant</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#x_001.x_001">
<dcterms:description>Proportion of IP3 receptor subunits with Ca inactivation site bound.</dcterms:description>
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<rdf:Description rdf:about="#IP3.IP3">
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<dcterms:description>Concentration of IP3 in the cytosol.</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#IP3.time">
<dcterms:description>Time domain</dcterms:description>
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<rdf:Description rdf:about="#Ca_i.J1">
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<semsim:name>IP3 Ca channel</semsim:name>
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</rdf:Description>
</semsim:hasSourceParticipant>
<dcterms:description>Flow of calcium from endoplasmic reticulum to cytosol across Ca-IP3 receptor.</dcterms:description>
<semsim:name>Flow of calcium from endoplasmic reticulum to cytosol</semsim:name>
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<dcterms:description>Outward flux of Ca from Cytosol</dcterms:description>
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<dcterms:description>Proportion of IP3 receptor subunits with Ca activation site bound.</dcterms:description>
</rdf:Description>
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<rdf:Description rdf:about="rdf:#ad8345d6-c32a-4ec5-99af-a95703959255">
<rdf:value>De Young and Keize assumed that only the state S_110 (one IP3 and
one activating Ca2+ bound) contributes to the conductance and that
all three subunits must be in this state for the channel to be
open. Thus the open probability is proportional to x^3_110.</rdf:value>
</rdf:Description>
</cmeta:comment>
<cmeta:comment>
<rdf:Description rdf:about="rdf:#c7e7447a-77f3-43fa-87fd-ec0a9fa1f8f6">
<rdf:value>In their model, De Young and Keizer utilise the Ca2+ conservation
condition to calculate the concentration of calcium ions in the
endoplasmic reticulum (Ca_ER).</rdf:value>
</rdf:Description>
</cmeta:comment>
</rdf:Description>
<rdf:Description rdf:about="#probability_of_an_open_IP3_receptor_channel.P_open">
<dcterms:description>IP3 receptor/Ca channel open probability.</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#receptor_dissociation_constants.IP3_cold">
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</rdf:Description>
<rdf:Description rdf:about="#fluxes.x_000">
<dcterms:description>Proportion of IP3 receptor subunits with all receptors unbound.</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#IP3.v4">
<dcterms:description>Maximum rate of IP3 production.</dcterms:description>
</rdf:Description>
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<semsim:AnnotatorName>Christopher Thompson</semsim:AnnotatorName>
<semsim:ModelDescription>A single-pool inositol 1,4,5-triphosphate-receptor-based model for agonist-stimulated oscillations in Ca 2+ concentration</semsim:ModelDescription>
</rdf:Description>
<rdf:Description rdf:about="#x_001.V1">
<dcterms:description>Change in free Ca concentration from Ca binding to unbound subunits and dissociation of Ca from bound inhibition receptor.</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#Ca_i.k3">
<dcterms:description>Activation constant for ATP-Ca pump</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#Ca_i.J2">
<semsim:isComputationalComponentFor>
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<rdf:Description rdf:about="#entity_4">
<semsim:name>IP3 Ca channel</semsim:name>
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</semsim:hasMediatorParticipant>
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</rdf:Description>
</semsim:hasSourceParticipant>
<dcterms:description>Flow of calcium from cytosol to endoplasmic reticulum across Ca-IP3 channel.</dcterms:description>
<semsim:name>Flow of calcium from cytosol to endoplasmic reticulum</semsim:name>
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</semsim:physicalPropertyOf>
<semsim:hasPhysicalDefinition rdf:resource="http://identifiers.org/opb/OPB_00593" />
</rdf:Description>
</semsim:isComputationalComponentFor>
<dcterms:description>Cytosol intake of Ca</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#probability_of_an_open_IP3_receptor_channel.d5">
<dcterms:description>Ca receptor dissociation constant (activation)</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#probability_of_an_open_IP3_receptor_channel.IP3">
<semsim:isComputationalComponentFor>
<rdf:Description rdf:about="#property_11">
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</semsim:isComputationalComponentFor>
<dcterms:description>Concentration of IP3 in the cytosol.</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#x_010.time">
<dcterms:description>Time domain</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#fluxes.x_001">
<dcterms:description>Proportion of IP3 receptor subunits with Ca inactivation site bound.</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#x_000.time">
<dcterms:description>Time domain</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#Ca_i.v1">
<dcterms:description>Max Ca channel flux</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#receptor_dissociation_constants.K_d1">
<semsim:isComputationalComponentFor>
<rdf:Description rdf:about="#property_5">
<semsim:hasPhysicalDefinition rdf:resource="http://identifiers.org/opb/OPB_00340" />
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</semsim:isComputationalComponentFor>
</rdf:Description>
<rdf:Description rdf:about="#receptor_dissociation_constants.d5">
<dcterms:description>Ca receptor dissociation constant (activation)</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="#IP3.Ir">
<dcterms:description>IP3 loss rate constant</dcterms:description>
</rdf:Description>
<rdf:Description rdf:about="http://www.cellml.org/cellml/1.0#mitochondrial_model_1992">
<dc:title>The De Young-Keizer 1992 model of oscillatory calcium release through
the IP3 stimulated channel</dc:title>
<cmeta:bio_entity>IP3 Receptor</cmeta:bio_entity>
<cmeta:comment>
<rdf:Description rdf:about="rdf:#33e862af-6f1a-4629-8913-c316c5475ba0">
<dc:creator rdf:resource="rdf:#c0eeae3b-cf1e-4daf-9e58-b50ee1ca7a3d" vCard:FN="" />
<rdf:value>The binding kinetics of IP3 and the activation of the receptor by Ca2+ are rapid, ensuring rapid release of Ca2+ after an IP3 pulse. This allows the number of receptor subunit states in the model to be reduced by four. We can eliminate the four receptor subunit states with IP3 bound (S_111, S_100, S_101, S_100). This leaves the reduced system outlined below.</rdf:value>
</rdf:Description>
</cmeta:comment>
<bqs:reference>
<rdf:Description rdf:about="rdf:#0f182932-7b2c-4005-bb19-558e9f8cb9e7" bqs:Pubmed_id="1329108">
<bqs:JournalArticle>
<rdf:Description rdf:about="rdf:#8279b5b4-917b-45f3-9464-03d1fda3688a" bqs:volume="89" bqs:first_page="9895" bqs:last_page="9899">
<dc:creator>
<rdf:Seq rdf:about="rdf:#2faff9c3-2816-4201-9df0-b95ab7092547">
<rdf:li>
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<vCard:Family>De Young</vCard:Family>
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<dc:title>A single-pool inositol 1,4,5-triphosphate-receptor-based model for agonist-stimulated oscillations in Ca 2+ concentration</dc:title>
<bqs:Journal>
<rdf:Description rdf:about="rdf:#87b5dced-3171-44e3-a868-766d9876bcb8">
<dc:title>Proceedings of the National Academy of Science, USA</dc:title>
</rdf:Description>
</bqs:Journal>
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<rdf:li>calcium dynamics</rdf:li>
<rdf:li>electrophysiology</rdf:li>
<rdf:li>signal transduction</rdf:li>
<rdf:li>ip3 receptor</rdf:li>
<rdf:li>IP3 Receptor</rdf:li>
</rdf:Bag>
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<dcterms:description>Cytosolic free Ca concentration</dcterms:description>
</rdf:Description>
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<dc:publisher>The University of Auckland, Bioengineering Institute</dc:publisher>
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<vCard:Orgname>The University of Auckland</vCard:Orgname>
<vCard:Orgunit>The Bioengineering Research Group</vCard:Orgunit>
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<rdf:value>Fixed link to diagram.</rdf:value>
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<rdf:value>The new version of this model has been re-coded to remove the reaction element and replace it with a simple MathML description of the model reaction kinetics. This is thought to be truer to the original publication, and information regarding the enzyme kinetics etc will later be added to the metadata through use of an ontology.
The model runs in the PCEnv simulator and gives a nice curved output... But not the spiked output published in the original paper.</rdf:value>
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<dcterms:description>Ca concentration in the endoplasmic reticulum.</dcterms:description>
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<dcterms:alternative>IP3 receptor/channel subunit with 3 unoccupied binding sites</dcterms:alternative>
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<dcterms:description>Ca leak flux constant</dcterms:description>
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<dcterms:description>Ca receptor dissociation constant (activation)</dcterms:description>
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<dcterms:description>Ca receptor dissociation constant (activation)</dcterms:description>
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<dcterms:description>Dissociation constant for Ca stimulation of IP3 production.</dcterms:description>
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<rdf:value>Ca2+ feedback on the production of inositol 1,4,5-triphosphate (IP3) is described by the equation below, where alpha has a value between 0 and 1.</rdf:value>
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<dcterms:description>Ca receptor binding constant (inhibition)</dcterms:description>
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<dcterms:alternative>IP3 receptor/channel subunit with an occupied Ca2+ inactivation
binding site</dcterms:alternative>
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<dcterms:description>Time domain</dcterms:description>
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<dcterms:description>Max Ca uptake</dcterms:description>
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<dcterms:description>Ca receptor binding constant (activation)</dcterms:description>
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<dcterms:description>Ca receptor binding constant (activation)</dcterms:description>
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<dcterms:description>Volume ratio of endoplasmic reticulum and cytosol</dcterms:description>
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<dcterms:description>Ca receptor binding constant (activation)</dcterms:description>
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<dcterms:description>Proportion of IP3 receptor subunits with Ca activation site bound.</dcterms:description>
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<dcterms:alternative>IP3 receptor/channel subunit with an occupied Ca2+ activation binding
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<dcterms:description>IP3 receptor/Ca channel open probability.</dcterms:description>
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<dcterms:description>Total Ca concentration in the cytosol</dcterms:description>
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<dcterms:description>Volume ratio of endoplasmic reticulum and cytosol</dcterms:description>
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<dcterms:description>Ca receptor dissociation constant (inhibition)</dcterms:description>
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<dcterms:description>Ca receptor binding constant (inhibition)</dcterms:description>
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<rdf:value>Cytoplasmic oscillations in Ca2+ concentration are described by the
equation below where Ca_i is the cytosolic free Ca2+ concentration,
J1 is the outward flux of Ca2+ and J2 is the inward flux of Ca2+.</rdf:value>
</rdf:Description>
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<dcterms:description>Ca receptor binding constant (inhibition)</dcterms:description>
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<dcterms:description>Change in free Ca concentration from Ca binding to unbound subunits and dissociation of Ca from bound inhibition receptor.</dcterms:description>
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<dcterms:description>Ca receptor dissociation constant (activation)</dcterms:description>
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</model>
