Rendering of the source text

<?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:  
 
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<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&amp;db=PubMed&amp;list_uids=8968617&amp;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>

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&#13;
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        Keizer and Levine's 1996 model of a gating scheme for ryanodine 
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