<?xml version='1.0' encoding='utf-8'?>
<!-- FILE : keizer_model_1996.xml
CREATED : 18th May 2007
LAST MODIFIED : 18th May 2007
AUTHOR : Catherine Lloyd
Bioengineering Institute
The University of Auckland
MODEL STATUS : This model conforms to the CellML 1.1 Specification.
DESCRIPTION : This file contains a CellML description of Keizer and Levine's
1996 model of ryanodine receptor adaptation and Cai2+-induced Cai2+ release-dependent Cai2+ oscillations.
CHANGES:
--><model xmlns="http://www.cellml.org/cellml/1.0#" xmlns:cmeta="http://www.cellml.org/metadata/1.0#" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bqs="http://www.cellml.org/bqs/1.0#" xmlns:cellml="http://www.cellml.org/cellml/1.0#" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#" cmeta:id="keizer_model_1996" name="keizer_levine_1996_version01">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
<articleinfo>
<title>RyR Adaptation and Ca2+ Oscillations</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>
The ryanodine receptor (RyR) from cardiac cells and skeletal muscle undergoes a Ca<superscript>2+</superscript>-dependent process called adaptation. Adaptation occurs during the slow, spontaneous decrease in the open probability of a channel after it has been rapidly activated by a pulse of cytosolic calcium ([Ca<superscript>2+</superscript>]<subscript>i</subscript>). RyR activation occurs within milliseconds, whereas inactivation occurs on a timescale of a few seconds. The RyR is said to have "adapted" during inactivation because a subsequent increase in [Ca<superscript>2+</superscript>]<subscript>i</subscript> produces a nearly identical rise in the open probability.
</para>
<para>
In their 1996 paper, Joel Keizer and Leslie Levine develop a simplified model that mimics the "adaptation" of the RyR, and they investigate its significance for Ca<superscript>2+</superscript>-induced Ca<superscript>2+</superscript> release and Ca<superscript>2+</superscript> oscillations in cardiac cells. The mechanism used to mimic adaptation of the RyR is shown schematically in <xref linkend="fig_reaction_diagram"/> below. States C1 and C2 are closed states and O1 and O2 are open states. Transitions from C1 to O1 and from O1 to O2 are assumed to be Ca<superscript>2+</superscript>-dependent. These steps correspond to the phenomenon of Ca<superscript>2+</superscript>-induced Ca<superscript>2+</superscript> release (CICR). To analyse the mechanism in <xref linkend="fig_reaction_diagram"/>, Keizer and Levine translated the schematic diagram into kinetic equations. In addition, they test these equations in a closed-cell kinetic model, and they find that RyR adaptation can cause Ca<superscript>2+</superscript> oscillations. However, in an open-cell, CICR, not RyR adaptation, produces Ca<superscript>2+</superscript> oscillations.
</para>
<para>
The complete original paper reference is cited below:
</para>
<para>
<ulink url="http://www.biophysj.org/cgi/content/abstract/71/6/3477">Ryanodine Receptor Adaptation and Ca<superscript>2+</superscript>-Induced Ca<superscript>2+</superscript> Release-Dependent Ca<superscript>2+</superscript> Oscillations</ulink>, Joel Keizer and Leslie Levine, 1996, <ulink url="http://www.biophysj.org/">
<emphasis>Biophysical Journal</emphasis>
</ulink>, 71, 3477-3487. <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8968617&dopt=Abstract">PubMed ID: 8968617</ulink>
</para>
<para>
The raw CellML description of the kinetic model of cardiac RyR adaptation can be downloaded in various formats as described in <xref linkend="sec_download_this_model"/>.
</para>
<informalfigure float="0" id="fig_reaction_diagram">
<mediaobject>
<imageobject>
<objectinfo>
<title>Schematic diagram of the RyR model</title>
</objectinfo>
<imagedata fileref="keizer_1996.png"/>
</imageobject>
</mediaobject>
<caption>Schematic diagram of transitions among the four states of the RyR used to describe adaptation. States C1 and C2 are closed states and O1 and O2 represent open states, assumed to have the same single-channel conductance. The <emphasis>k</emphasis> are rate constants: only steps <emphasis>a</emphasis> and <emphasis>b</emphasis> are Ca<superscript>2+</superscript> dependent.</caption>
</informalfigure>
</sect1>
</article>
</documentation>
<!--
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.
-->
<!--
Below, we define some additional units for association with variables and
constants within the model. The identifiers are fairly self-explanatory.
-->
<units name="micromolar">
<unit units="mole" prefix="micro"/>
<unit units="litre" exponent="-1"/>
</units>
<units name="micromolar_3">
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<unit units="second" exponent="-1"/>
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<units name="forth_order_rate_constant">
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<units name="fifth_order_rate_constant">
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<!--
The "environment" component is used to declare variables that are used by
all or most of the other components, in this case just "time".
-->
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<rdf:RDF>
<rdf:Bag rdf:about="rdf:#7c9b148e-ed9f-4a87-9dff-53ccad85198e">
<rdf:li>calcium dynamics</rdf:li>
<rdf:li>ryanodine receptor</rdf:li>
<rdf:li>oscillator</rdf:li>
<rdf:li>Cardiac Myocyte</rdf:li>
<rdf:li>electrophysiology</rdf:li>
<rdf:li>cardiac</rdf:li>
<rdf:li>ryanodine receptors</rdf:li>
<rdf:li>cicr</rdf:li>
</rdf:Bag>
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<dcterms:alternative>
Open state on a slow time scale
</dcterms:alternative>
<dc:title>P_O_slow</dc:title>
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<dcterms:modified rdf:resource="rdf:#8a4d8d2f-ef42-4f25-9531-94f56be400c8"/>
<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 but gives NaNs. </rdf:value>
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</rdf:Description>
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<dc:publisher>The University of Auckland, Bioengineering Institute</dc:publisher>
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<vCard:Given>Leslie</vCard:Given>
<vCard:Family>Levine</vCard:Family>
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<dc:creator rdf:resource="rdf:#195fcc82-f0ed-47a2-af62-dcbfef65cb49"/>
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<rdf:Description rdf:about="rdf:#7a0bfaaa-0770-4d84-92e4-fd4c373be683">
<dcterms:W3CDTF>1996-12-01</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="rdf:#64ff61b2-1ca2-42dc-acd0-0a3aa8e41732">
<rdf:type rdf:resource="http://imc.org/vCard/3.0#internet"/>
<rdf:value>c.lloyd@auckland.ac.nz</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="rdf:#63db43d4-8f44-43f9-96fd-fc56c5f78ea3">
<bqs:Pubmed_id>8968617</bqs:Pubmed_id>
<bqs:JournalArticle rdf:resource="rdf:#7609c86a-2091-4bef-b8a2-1f23e16a414d"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#e16911fc-e75e-4939-938f-85e6b5d1fe0b">
<dc:title>Biophysical Journal</dc:title>
</rdf:Description>
<rdf:Description rdf:about="#keizer_model_1996">
<dc:title>
Keizer and Levine's 1996 model of a gating scheme for ryanodine
receptors.
</dc:title>
<cmeta:bio_entity>Cardiac Myocyte</cmeta:bio_entity>
<cmeta:comment rdf:resource="rdf:#8ab1826e-034b-4ddb-8c7d-4a601a818731"/>
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<bqs:reference rdf:resource="rdf:#63db43d4-8f44-43f9-96fd-fc56c5f78ea3"/>
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<dc:creator rdf:resource="rdf:#f92b8ad0-4a12-4226-9994-67dbfa6c454e"/>
<dc:title>Ryanodine Receptor Adaptation and Ca2+-Induced Ca2+
Release-Dependent Ca2+ Oscillations</dc:title>
<bqs:volume>71</bqs:volume>
<bqs:first_page>3477</bqs:first_page>
<bqs:Journal rdf:resource="rdf:#e16911fc-e75e-4939-938f-85e6b5d1fe0b"/>
<dcterms:issued rdf:resource="rdf:#7a0bfaaa-0770-4d84-92e4-fd4c373be683"/>
<bqs:last_page>3487</bqs:last_page>
</rdf:Description>
<rdf:Description rdf:about="/P_O2">
<dcterms:alternative>Open state 2</dcterms:alternative>
<dc:title>P_O2</dc:title>
</rdf:Description>
<rdf:Description rdf:about="/P_O1">
<dcterms:alternative>Open state 1</dcterms:alternative>
<dc:title>P_O1</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#22a7b94f-50b8-4b8f-87d6-92a070439d0c">
<vCard:Given>Joel</vCard:Given>
<vCard:Family>Keizer</vCard:Family>
</rdf:Description>
<rdf:Description rdf:about="/Cai">
<dcterms:alternative>
Intracellular calcium concentration in a closed cell
</dcterms:alternative>
<dc:title>Cai</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#09ceb32b-2f01-428e-a562-6c0bf2ed4ab4">
<vCard:N rdf:resource="rdf:#6f2f561a-e4b3-4ba4-85bc-e916457d14af"/>
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<rdf:Description rdf:about="rdf:#04513b89-1af7-4da7-8884-ec2a51499eef">
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<vCard:N rdf:resource="rdf:#22a7b94f-50b8-4b8f-87d6-92a070439d0c"/>
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<rdf:Description rdf:about="rdf:#5fb7f618-b462-4e08-b6ef-a469dfda5318">
<dc:subject rdf:resource="rdf:#482ff6ca-7779-4582-b3ba-e747392d4e9f"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#6f2f561a-e4b3-4ba4-85bc-e916457d14af">
<vCard:Given>Catherine</vCard:Given>
<vCard:Family>Lloyd</vCard:Family>
<vCard:Other>May</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#8ab1826e-034b-4ddb-8c7d-4a601a818731">
<dc:creator rdf:resource="rdf:#58957513-8dd3-4db4-b0a4-67b8fa33a2c1"/>
<rdf:value>This is the CellML description of Keizer and Levine's 1996 model of a
gating scheme for ryanodine receptors in cardiac muscle.</rdf:value>
</rdf:Description>
<rdf:Description rdf:about="/P_C2">
<dcterms:alternative>Closed state 2</dcterms:alternative>
<dc:title>P_C2</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#8a4d8d2f-ef42-4f25-9531-94f56be400c8">
<dcterms:W3CDTF>2007-06-05T09:35:57+12:00</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="rdf:#58957513-8dd3-4db4-b0a4-67b8fa33a2c1">
<vCard:FN>Catherine Lloyd</vCard:FN>
</rdf:Description>
<rdf:Description rdf:about="/P_C1">
<dcterms:alternative>Closed state 1</dcterms:alternative>
<dc:title>P_C1</dc:title>
</rdf:Description>
<rdf:Description rdf:about="rdf:#f2ea0d58-f986-4d50-9239-1f50334c862d">
<vCard:ORG rdf:resource="rdf:#2dff1af3-376a-446c-9bd7-e0ad62d2560c"/>
<vCard:EMAIL rdf:resource="rdf:#64ff61b2-1ca2-42dc-acd0-0a3aa8e41732"/>
<vCard:N rdf:resource="rdf:#d63716c2-15ed-4f63-b227-f7db6076a098"/>
</rdf:Description>
<rdf:Description rdf:about="rdf:#d63716c2-15ed-4f63-b227-f7db6076a098">
<vCard:Given>Catherine</vCard:Given>
<vCard:Family>Lloyd</vCard:Family>
<vCard:Other>May</vCard:Other>
</rdf:Description>
<rdf:Description rdf:about="rdf:#4d2bff11-5b03-4771-aac4-28e77e821640">
<dcterms:W3CDTF>2007-05-18</dcterms:W3CDTF>
</rdf:Description>
<rdf:Description rdf:about="rdf:#2dff1af3-376a-446c-9bd7-e0ad62d2560c">
<vCard:Orgname>The University of Auckland</vCard:Orgname>
<vCard:Orgunit>The Bioengineering Institute</vCard:Orgunit>
</rdf:Description>
<rdf:Description rdf:about="rdf:#482ff6ca-7779-4582-b3ba-e747392d4e9f">
<bqs:subject_type>keyword</bqs:subject_type>
<rdf:value rdf:resource="rdf:#7c9b148e-ed9f-4a87-9dff-53ccad85198e"/>
</rdf:Description>
</rdf:RDF>
</model>
