Location: Shorten, Wall, 2000 @ ce6d9c910614 / shorten_wall_2000.cellml

Author:
Hanne <Hanne@hanne-nielsens-macbook.local>
Date:
2009-12-14 15:46:42+13:00
Desc:
Added images in ai and svg format, removed non pub med references
Permanent Source URI:
https://models.fieldml.org/workspace/shorten_wall_2000/rawfile/ce6d9c910614a9689386f9af85e5b28a7f832112/shorten_wall_2000.cellml

<?xml version='1.0' encoding='utf-8'?>
<!--  FILE :  shorten_model_2000.xml

CREATED :  3rd December 2002

LAST MODIFIED : 9th April 2003

AUTHOR :  Catherine Lloyd
          Bioengineering Institute
          The University of Auckland
          
MODEL STATUS :  This model conforms to the CellML 1.0 Specification released on
10th August 2001, and the 16/01/2002 CellML Metadata 1.0 Specification.

DESCRIPTION :  This file contains a CellML description of Shorten and Wall's 2000 Hodgkin-Huxley type mathematical model of bursting oscillations in pituitary corticotrophs. 

CHANGES:  
  09/04/2003 - AAC - Added publication date information.  
  
--><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="shorten_wall_2000_version01" name="shorten_wall_2000_version01">
<documentation xmlns="http://cellml.org/tmp-documentation">
<article>
  <articleinfo>
  <title>A Hodgkin-Huxley Model Exhibiting Bursting Oscillations</title>
  <author>
    <firstname>Catherine</firstname>
          <surname>Lloyd</surname>
    <affiliation>
      <shortaffil>Bioengineering Institute, University of Auckland</shortaffil>
    </affiliation>
  </author>
</articleinfo>
  <section id="sec_status">
    <title>Model Status</title>
    <para>
            This is the original unchecked version of the model imported from the previous
            CellML model repository, 24-Jan-2006.
          </para>
  </section>
  <sect1 id="sec_structure">
<title>Model Structure</title>

<para>
Like many other types of excitable cell, pituitary corticotrophs display bursting behaviour.  These electrical bursts consist of Ca<superscript>2+</superscript>-carrying action potentials, alternating with silent phases of repolarisation.  Spikes representing sudden membrane depolarisation are often accompanied by oscillations in cytosolic Ca<superscript>2+</superscript> concentration ([Ca<superscript>2+</superscript>]<subscript>i</subscript>), and also in corticotrophs, they are followed by small oscillations in the membrane potential.  
</para>

<para>
The mechanisms underlying this bursting behaviour have been the subject of several studies.  In this study described here, Paul R. Shorten and David J.N. Wall develop a Hodgkin-Huxley type mathematical model (for the original model description see <ulink url="${HTML_EXMPL_HHSA_INTRO}">The Hodgkin-Huxley Squid Axon Model, 1952</ulink>) of pituitary corticotrophs.  The model includes the major plasma membrane ionic currents and the associated intracellular Ca<superscript>2+</superscript> dynamics (see <xref linkend="fig_cell_diagram"/> below).  The bursting process is driven by the slow modulation of the endoplasmic reticulum (ER) Ca<superscript>2+</superscript> concentration ([Ca<superscript>2+</superscript>]<subscript>er</subscript>), giving rise to a slow component in [Ca<superscript>2+</superscript>]<subscript>i</subscript>.  This then gives rise to the electrical bursting via a Ca<superscript>2+</superscript>-activated potassium current (<emphasis>I<subscript>K-Ca</subscript>
          </emphasis>).  Model simulations showed that bursting frequency is dependent on the ER Ca<superscript>2+</superscript> storage capacity, the Ca<superscript>2+</superscript> transport mechanisms, and the activation of a Ca<superscript>2+</superscript>-activated K<superscript>+</superscript> current. 
</para>

<para>
Excitable cells display a wide range of different types of bursting behaviours.  Shorten and Wall discovered that their model exhibits a novel form of bursting due to bistability between two stable oscillatory solutions.  Due to the bifurcations involved, this type of bursting is called 'fold cycle/fold cycle' bursting.  In their paper, which is fully referenced below, Shorten and Wall aim to highlight interesting modes of bursting in Hodgkin-Huxley type mathematical models and elucidate their underlying mechanisms.  They especially emphasise how small parameter changes can cause large changes in the model behaviour.
</para>

<para>
A Hodgkin-Huxley Model Exhibiting Bursting Oscillations, Paul R. Shorten and David J.N. Wall, 2000, <emphasis>Bulletin of Mathematical Biology</emphasis>, 62, 695-715.   <ulink url="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&amp;db=PubMed&amp;list_uids=10938629&amp;dopt=Abstract">PubMed ID: 10938629</ulink>  
</para>


<informalfigure float="0" id="fig_cell_diagram">
<mediaobject>
  <imageobject>
    <objectinfo>
      <title>cell schematic for the model</title>
    </objectinfo>
    <imagedata fileref="shorten_wall_2000.png"/>
  </imageobject>
</mediaobject>
<caption>Schematic diagram of a pituitary corticotroph cell showing the transmembrane ionic currents and the intracellular Ca<superscript>2+</superscript> dynamics captured by the mathematical model.  Arrows indicate ionic channels and pumps.  <emphasis>I<subscript>Ca-L</subscript>
            </emphasis> represents an L-type Ca<superscript>2+</superscript> current responsible for most of the Ca<superscript>2+</superscript> influx during an action potential.  <emphasis>I<subscript>Ca-T</subscript>
            </emphasis> is a T-type voltage-sensitive Ca<superscript>2+</superscript> current.  A voltage-sensitive K<superscript>+</superscript> current, <emphasis>I<subscript>K-DR</subscript>
            </emphasis>, is mainly responsible for action potential repolarisation.  A Ca<superscript>2+</superscript>-activated K<superscript>+</superscript> current, <emphasis>I<subscript>K-Ca</subscript>
            </emphasis>, is essential for bursting behaviour.  The remaining leak current, <emphasis>I<subscript>leak</subscript>
            </emphasis>, represents all other ionic fluxes across the plasma membrane which are not specifically described by the model.  <emphasis>J<subscript>eff</subscript>
            </emphasis> and <emphasis>J<subscript>up</subscript>
            </emphasis> are the ER and plasma membrane Ca<superscript>2+</superscript>-ATPase pumps, and <emphasis>J<subscript>rel</subscript>
            </emphasis> represents the ER Ca<superscript>2+</superscript> leakage term.  Within the ER and the cytosol, significant portions of Ca<superscript>2+</superscript> are bound to buffers, denoted by B<subscript>er</subscript> and B<subscript>c</subscript> respectively.</caption>
</informalfigure>

</sect1>
</article>
</documentation>
  
  
  <!--
    Below, we define some additional units for association with variables and
    constants within the model. The identifiers are fairly self-explanatory.
  -->
  
  <units name="millisecond">
    <unit units="second" prefix="milli"/>
  </units>
  
  <units name="millivolt">
    <unit units="volt" prefix="milli"/>
  </units>
  
  <units name="picoL">
    <unit units="litre" prefix="pico"/>
  </units>
  
  <units name="picoL_per_millisecond">
    <unit units="picoL"/>
    <unit units="millisecond" exponent="-1.0"/>
  </units>
  
  <units name="millimolar">
    <unit units="mole" prefix="milli"/>
    <unit units="litre" exponent="-1"/>
  </units>
  
  <units name="millimolar_per_millisecond">
    <unit units="millimolar"/>
    <unit units="millisecond" exponent="-1.0"/>
  </units>
  
  <units name="molar">
    <unit units="mole"/>
    <unit units="litre" exponent="-1"/>
  </units>
  
  <units name="micromolar">
    <unit units="mole" prefix="micro"/>
    <unit units="litre" exponent="-1"/>
  </units>
  
  <units name="micromolar_micrometre_per_millisecond">
    <unit units="micromolar"/>
    <unit units="micrometre"/>
    <unit units="millisecond" exponent="-1"/>
  </units>
  
  <units name="micromolar_picoL_per_millisecond">
    <unit units="micromolar"/>
    <unit units="picoL"/>
    <unit units="millisecond" exponent="-1"/>
  </units>
  
  <units name="micromolar_micrometre_per_millisecond_per_picoA">
    <unit units="micromolar"/>
    <unit units="micrometre"/>
    <unit units="millisecond" exponent="-1"/>
    <unit units="ampere" prefix="pico" exponent="-1"/>
  </units>
  
  <units name="nanoS_per_millimolar">
    <unit units="siemens" prefix="nano"/>
    <unit units="molar" prefix="milli" exponent="-1"/>
  </units>
  
  <units name="picoF">
    <unit units="farad" prefix="pico"/>
  </units>
  
  <units name="nanoS">
    <unit units="siemens" prefix="nano"/>
  </units>
  
  <units name="microA_per_cm2">
    <unit units="ampere" prefix="micro"/>
    <unit units="metre" prefix="centi" exponent="-2.0"/>
  </units>
  
  <units name="micrometre">
    <unit units="metre" prefix="micro"/>
  </units>
  
  <units name="per_micrometre">
    <unit units="micrometre" exponent="-1.0"/>
  </units>
  
  <units name="joule_per_kilomole_kelvin">
    <unit units="joule"/>
    <unit units="mole" prefix="kilo" exponent="-1"/>
    <unit units="kelvin" exponent="-1"/>
  </units>
  
  <units name="coulomb_per_mole">
    <unit units="coulomb"/>
    <unit units="mole" exponent="-1"/>
  </units>
  
  <component name="environment">
    <variable units="second" public_interface="out" name="time"/>
    <variable units="picoL" public_interface="out" name="V_cell" initial_value="1.77"/>
    <variable units="millimolar" public_interface="out" name="Ca_e" initial_value="20.0"/>
    <variable units="millimolar" public_interface="out" name="K_e" initial_value="5.6"/>
    <variable units="millimolar" public_interface="out" name="K_i" initial_value="140.0"/>
    <variable units="millivolt" public_interface="out" name="V_tau" initial_value="-60.0"/>
    <variable units="millivolt" public_interface="out" name="k_tau" initial_value="22.0"/>
  </component>
  
  <component name="membrane">
    <variable units="millivolt" public_interface="out" name="V"/>
    <variable units="joule_per_kilomole_kelvin" public_interface="out" name="R" initial_value="8.314"/>
    <variable units="kelvin" public_interface="out" name="T" initial_value="310.0"/>
    <variable units="coulomb_per_mole" public_interface="out" name="F" initial_value="96845.0"/>
    
    <variable units="picoF" name="Cm" initial_value="7.0"/>
    
    <variable units="second" public_interface="in" name="time"/>
    <variable units="microA_per_cm2" public_interface="in" name="i_Ca_L"/>
    <variable units="microA_per_cm2" public_interface="in" name="i_Ca_T"/>
    <variable units="microA_per_cm2" public_interface="in" name="i_K_DR"/>
    <variable units="microA_per_cm2" public_interface="in" name="i_K_Ca"/>
    <variable units="microA_per_cm2" public_interface="in" name="i_leak"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply id="membrane_voltage_diff_eq">
        <eq/>
        <apply>
          <diff/>
          <bvar>
            <ci> time </ci>
          </bvar>
          <ci> V </ci>
        </apply>
        <apply>
          <divide/>
          <apply>
            <minus/>
            <apply>
              <plus/>
              <ci> i_Ca_L </ci>
              <ci> i_Ca_T </ci>
              <ci> i_K_DR </ci>
              <ci> i_K_Ca </ci>
              <ci> i_leak </ci>
            </apply>
          </apply>
          <ci> Cm </ci>
        </apply>
      </apply>
    </math>
  </component>
  
  <component name="L_type_calcium_current">
    <variable units="microA_per_cm2" public_interface="out" name="i_Ca_L"/>
    <variable units="millivolt" public_interface="out" name="V_Ca"/>
    
    <variable units="nanoS_per_millimolar" name="g_Ca_L" initial_value="9.0"/> 
   
    <variable units="second" public_interface="in" private_interface="out" name="time"/>
    <variable units="millivolt" public_interface="in" private_interface="out" name="V"/>
    <variable units="millivolt" public_interface="in" private_interface="out" name="V_tau"/>
    <variable units="millivolt" public_interface="in" private_interface="out" name="k_tau"/>
              
    <variable units="joule_per_kilomole_kelvin" public_interface="in" name="R"/>
    <variable units="kelvin" public_interface="in" name="T"/>
    <variable units="coulomb_per_mole" public_interface="in" name="F"/>
    <variable units="millimolar" public_interface="in" name="Ca_e"/>
    <variable units="millimolar" public_interface="in" name="Ca_i"/>
    
    <variable units="dimensionless" private_interface="in" name="m_L"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply id="i_Ca_L_calculation">
        <eq/>
        <ci> i_Ca_L </ci>
        <apply>
          <times/>
          <ci> g_Ca_L </ci>
          <apply>
            <power/>
            <ci> m_L </ci>
            <cn cellml:units="dimensionless"> 2.0 </cn>
          </apply>
          <ci> V_Ca </ci>
        </apply>
      </apply>
      
      <apply id="V_Ca_calculation">
        <eq/>
        <ci> V_Ca </ci>
        <apply>
          <times/>
          <ci> V </ci>
          <apply>
            <divide/>
            <apply>
              <times/>
              <apply>
                <minus/>
                <ci> Ca_i </ci>
                <ci> Ca_e </ci>
              </apply>
              <apply>
                <exp/>
                <apply>
                  <times/>
                  <apply>
                    <minus/>
                    <cn cellml:units="dimensionless"> 2.0 </cn>
                  </apply>
                  <apply>
                    <divide/>
                    <apply>
                      <times/>
                      <ci> F </ci>
                      <ci> V </ci>
                    </apply>
                    <apply>
                      <times/>
                      <ci> R </ci>
                      <ci> T </ci>
                    </apply>
                  </apply>
                </apply>
              </apply>
            </apply>
            <apply>
              <minus/>
              <cn cellml:units="dimensionless"> 1.0 </cn>
              <apply>
                <exp/>
                <apply>
                  <times/>
                  <apply>
                    <minus/>
                    <cn cellml:units="dimensionless"> 2.0 </cn>
                  </apply>
                  <apply>
                    <divide/>
                    <apply>
                      <times/>
                      <ci> F </ci>
                      <ci> V </ci>
                    </apply>
                    <apply>
                      <times/>
                      <ci> R </ci>
                      <ci> T </ci>
                    </apply>
                  </apply>
                </apply>
              </apply>  
            </apply> 
          </apply>
        </apply>
      </apply>
    </math>
  </component> 
  
  <component name="L_type_calcium_current_m_gate">
    <variable units="dimensionless" public_interface="out" name="m_L"/>
    
    <variable units="dimensionless" name="m_L_infinity"/>
    <variable units="millisecond" name="tau_m_L"/>
    <variable units="millisecond" name="tau_m_L_max" initial_value="27.0"/>
    <variable units="millivolt" name="V_m_L" initial_value="-18.0"/>
    <variable units="millivolt" name="k_m_L" initial_value="12.0"/>
    
    <variable units="millivolt" public_interface="in" name="V"/>
    <variable units="millivolt" public_interface="in" name="V_tau"/>
    <variable units="millivolt" public_interface="in" name="k_tau"/>
    <variable units="second" public_interface="in" name="time"/>
   
    <math xmlns="http://www.w3.org/1998/Math/MathML">
     <apply id="m_L_diff_eq">
        <eq/>
       <apply>
          <diff/>
          <bvar>
            <ci> time </ci>
          </bvar>
          <ci> m_L </ci>
        </apply>
        <apply>
          <divide/>
          <apply>
            <minus/>
            <ci> m_L_infinity </ci>
            <ci> m_L </ci>
          </apply>
          <ci> tau_m_L </ci>
        </apply>
      </apply>
      
      <apply id="m_L_infinity_calculation">
        <eq/>
        <ci> m_L_infinity </ci>
        <apply>
          <divide/>
          <cn cellml:units="dimensionless"> 1.0 </cn>
          <apply>
            <plus/>
            <cn cellml:units="dimensionless"> 1.0 </cn>
            <apply>
              <exp/>
              <apply>
                <divide/>
                <apply>
                  <minus/>
                  <ci> V_m_L </ci>
                  <ci> V </ci>
                </apply>
                <ci> k_m_L </ci>
              </apply>
            </apply>    
          </apply>
        </apply>
      </apply>
      
      <apply id="tau_m_L_calculation">
        <eq/>
        <ci> tau_m_L </ci>
        <apply>
          <divide/>
          <ci> tau_m_L_max </ci>
          <apply>
            <plus/>
            <apply>
              <exp/>
              <apply>
                <divide/>
                <apply>
                  <minus/>
                  <ci> V </ci>
                  <ci> V_tau </ci>
                </apply>
                <ci> k_tau </ci>
              </apply>
            </apply>
            <apply>
              <times/>
              <cn cellml:units="dimensionless"> 2.0 </cn>
              <apply>
                <exp/>
                <apply>
                  <divide/>
                  <apply>
                    <times/>
                    <cn cellml:units="dimensionless"> 2.0 </cn>
                    <apply>
                      <minus/>
                      <ci> V_tau </ci>
                      <ci> V </ci>
                    </apply>
                  </apply>
                  <ci> k_tau </ci>
                </apply>
              </apply>
            </apply>        
          </apply>
        </apply>
      </apply>
    </math>
  </component>
  
  <component name="T_type_calcium_current">
    <variable units="microA_per_cm2" public_interface="out" name="i_Ca_T"/>
    
    <variable units="nanoS_per_millimolar" name="g_Ca_T" initial_value="10.0"/>   
    <variable units="second" public_interface="in" private_interface="out" name="time"/>
    <variable units="millivolt" public_interface="in" private_interface="out" name="V"/>
    <variable units="millivolt" public_interface="in" private_interface="out" name="V_tau"/>
    <variable units="millivolt" public_interface="in" private_interface="out" name="k_tau"/>
   
    <variable units="millivolt" public_interface="in" name="V_Ca"/>          
    
    <variable units="dimensionless" private_interface="in" name="m_T"/>
    <variable units="dimensionless" private_interface="in" name="h_T"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply id="i_Ca_T_calculation">
        <eq/>
        <ci> i_Ca_T </ci>
        <apply>
          <times/>
          <ci> g_Ca_T </ci>
          <apply>
            <power/>
            <ci> m_T </ci>
            <cn cellml:units="dimensionless"> 2.0 </cn>
          </apply>
          <ci> h_T </ci>
          <ci> V_Ca </ci>
        </apply>
      </apply>
    </math>
  </component> 
  
  <component name="T_type_calcium_current_m_gate">
    <variable units="dimensionless" public_interface="out" name="m_T"/>
    
    <variable units="dimensionless" name="m_T_infinity"/>
    <variable units="millisecond" name="tau_m_T"/>
    <variable units="millisecond" name="tau_m_T_max" initial_value="10.0"/>
    <variable units="millivolt" name="V_m_T" initial_value="-30.0"/>
    <variable units="millivolt" name="k_m_T" initial_value="10.5"/>
    
    <variable units="millivolt" public_interface="in" name="V"/>
    <variable units="millivolt" public_interface="in" name="V_tau"/>
    <variable units="millivolt" public_interface="in" name="k_tau"/>
    <variable units="second" public_interface="in" name="time"/>
   
    <math xmlns="http://www.w3.org/1998/Math/MathML">
     <apply id="m_T_diff_eq">
        <eq/>
       <apply>
          <diff/>
          <bvar>
            <ci> time </ci>
          </bvar>
          <ci> m_T </ci>
        </apply>
        <apply>
          <divide/>
          <apply>
            <minus/>
            <ci> m_T_infinity </ci>
            <ci> m_T </ci>
          </apply>
          <ci> tau_m_T </ci>
        </apply>
      </apply>
      
      <apply id="m_T_infinity_calculation">
        <eq/>
        <ci> m_T_infinity </ci>
        <apply>
          <divide/>
          <cn cellml:units="dimensionless"> 1.0 </cn>
          <apply>
            <plus/>
            <cn cellml:units="dimensionless"> 1.0 </cn>
            <apply>
              <exp/>
              <apply>
                <divide/>
                <apply>
                  <minus/>
                  <ci> V_m_T </ci>
                  <ci> V </ci>
                </apply>
                <ci> k_m_T </ci>
              </apply>
            </apply>    
          </apply>
        </apply>
      </apply>
      
      <apply id="tau_m_T_calculation">
        <eq/>
        <ci> tau_m_T </ci>
        <apply>
          <divide/>
          <ci> tau_m_T_max </ci>
          <apply>
            <plus/>
            <apply>
              <exp/>
              <apply>
                <divide/>
                <apply>
                  <minus/>
                  <ci> V </ci>
                  <ci> V_tau </ci>
                </apply>
                <ci> k_tau </ci>
              </apply>
            </apply>
            <apply>
              <times/>
              <cn cellml:units="dimensionless"> 2.0 </cn>
              <apply>
                <exp/>
                <apply>
                  <divide/>
                  <apply>
                    <times/>
                    <cn cellml:units="dimensionless"> 2.0 </cn>
                    <apply>
                      <minus/>
                      <ci> V_tau </ci>
                      <ci> V </ci>
                    </apply>
                  </apply>
                  <ci> k_tau </ci>
                </apply>
              </apply>
            </apply>        
          </apply>
        </apply>
      </apply>
    </math>
  </component>
  
  <component name="T_type_calcium_current_h_gate">
    <variable units="dimensionless" public_interface="out" name="h_T"/>
    
    <variable units="dimensionless" name="h_T_infinity"/>
    <variable units="millisecond" name="tau_h_T" initial_value="15.0"/>
    <variable units="millivolt" name="V_h_T" initial_value="-57.0"/>
    <variable units="millivolt" name="k_h_T" initial_value="5.0"/>
    
    <variable units="millivolt" public_interface="in" name="V"/>
    <variable units="second" public_interface="in" name="time"/>
   
    <math xmlns="http://www.w3.org/1998/Math/MathML">
     <apply id="h_T_diff_eq">
        <eq/>
       <apply>
          <diff/>
          <bvar>
            <ci> time </ci>
          </bvar>
          <ci> h_T </ci>
        </apply>
        <apply>
          <divide/>
          <apply>
            <minus/>
            <ci> h_T_infinity </ci>
            <ci> h_T </ci>
          </apply>
          <ci> tau_h_T </ci>
        </apply>
      </apply>
      
      <apply id="h_T_infinity_calculation">
        <eq/>
        <ci> h_T_infinity </ci>
        <apply>
          <divide/>
          <cn cellml:units="dimensionless"> 1.0 </cn>
          <apply>
            <plus/>
            <cn cellml:units="dimensionless"> 1.0 </cn>
            <apply>
              <exp/>
              <apply>
                <divide/>
                <apply>
                  <minus/>
                  <ci> V </ci>
                  <ci> V_h_T </ci>
                </apply>
                <ci> k_h_T </ci>
              </apply>
            </apply>    
          </apply>
        </apply>
      </apply>
    </math>
  </component>
  
  <component name="voltage_sensitive_K_current">
    <variable units="microA_per_cm2" public_interface="out" name="i_K_DR"/>
    <variable units="millivolt" public_interface="out" name="V_K"/>
   
    <variable units="nanoS_per_millimolar" name="g_K_DR" initial_value="0.1"/>   
    <variable units="second" public_interface="in" private_interface="out" name="time"/>
    <variable units="millivolt" public_interface="in" private_interface="out" name="V"/>
              
    <variable units="joule_per_kilomole_kelvin" public_interface="in" name="R"/>
    <variable units="kelvin" public_interface="in" name="T"/>
    <variable units="coulomb_per_mole" public_interface="in" name="F"/>
    <variable units="millimolar" public_interface="in" name="K_e"/>
    <variable units="millimolar" public_interface="in" name="K_i"/>
    
    <variable units="dimensionless" private_interface="in" name="n"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply id="i_K_DR_calculation">
        <eq/>
        <ci> i_K_DR </ci>
        <apply>
          <times/>
          <ci> g_K_DR </ci>
          <ci> n </ci>
          <apply>
            <minus/>
            <ci> V </ci>
            <ci> V_K </ci>
          </apply>
        </apply>
      </apply>
      
      <apply id="V_K_calculation">
        <eq/>
        <ci> V_K </ci>
        <apply>
          <times/>
          <ci> V </ci>
          <apply>
            <divide/>
            <apply>
              <times/>
              <apply>
                <minus/>
                <ci> K_i </ci>
                <ci> K_e </ci>
              </apply>
              <apply>
                <exp/>
                <apply>
                  <times/>
                  <apply>
                    <minus/>
                    <cn cellml:units="dimensionless"> 1.0 </cn>
                  </apply>
                  <apply>
                    <divide/>
                    <apply>
                      <times/>
                      <ci> F </ci>
                      <ci> V </ci>
                    </apply>
                    <apply>
                      <times/>
                      <ci> R </ci>
                      <ci> T </ci>
                    </apply>
                  </apply>
                </apply>
              </apply>
            </apply>
            <apply>
              <minus/>
              <cn cellml:units="dimensionless"> 1.0 </cn>
              <apply>
                <exp/>
                <apply>
                  <times/>
                  <apply>
                    <minus/>
                    <cn cellml:units="dimensionless"> 1.0 </cn>
                  </apply>
                  <apply>
                    <divide/>
                    <apply>
                      <times/>
                      <ci> F </ci>
                      <ci> V </ci>
                    </apply>
                    <apply>
                      <times/>
                      <ci> R </ci>
                      <ci> T </ci>
                    </apply>
                  </apply>
                </apply>
              </apply>  
            </apply> 
          </apply>
        </apply>
      </apply>
    </math>
  </component> 
  
  <component name="voltage_sensitive_K_current_n_gate">
    <variable units="dimensionless" public_interface="out" name="n"/>
    
    <variable units="dimensionless" name="n_infinity"/>
    <variable units="millisecond" name="tau_n" initial_value="20.0"/>
    <variable units="millivolt" name="V_n" initial_value="-20.0"/>
    <variable units="millivolt" name="k_n" initial_value="4.5"/>
     
    <variable units="millivolt" public_interface="in" name="V"/>
    <variable units="second" public_interface="in" name="time"/>
   
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply id="n_diff_eq">
        <eq/>
        <apply>
          <diff/>
          <bvar>
            <ci> time </ci>
          </bvar>
          <ci> n </ci>
        </apply>
        <apply>
          <divide/>
          <apply>
            <minus/>
            <ci> n_infinity </ci>
            <ci> n </ci>
          </apply>
          <ci> tau_n </ci>
        </apply>
      </apply>
      
      <apply id="n_infinity_calculation">
        <eq/>
        <ci> n_infinity </ci>
        <apply>
          <divide/>
          <cn cellml:units="dimensionless"> 1.0 </cn>
          <apply>
            <plus/>
            <cn cellml:units="dimensionless"> 1.0 </cn>
            <apply>
              <exp/>
              <apply>
                <divide/>
                <apply>
                  <minus/>
                  <ci> V_n </ci>
                  <ci> V </ci>
                </apply>
                <ci> k_n </ci>
              </apply>
            </apply>    
          </apply>
        </apply>
      </apply>
    </math>
  </component> 
  
  <component name="Ca_activated_K_current">
    <variable units="microA_per_cm2" public_interface="out" name="i_K_Ca"/>
    
    <variable units="nanoS_per_millimolar" name="g_K_Ca" initial_value="0.09"/>
    <variable units="micromolar" name="Kc" initial_value="0.4"/>
         
    <variable units="second" public_interface="in" name="time"/>
    <variable units="millivolt" public_interface="in" name="V"/>
    <variable units="millivolt" public_interface="in" name="V_K"/>
    <variable units="millimolar" public_interface="in" name="Ca_i"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply id="i_K_Ca_calculation">
        <eq/>
        <ci> i_K_Ca </ci>
        <apply>
          <times/>
          <ci> g_K_Ca </ci>
          <apply>
            <divide/>
            <apply>
              <power/>
              <ci> Ca_i </ci>
              <cn cellml:units="dimensionless"> 4.0 </cn>
            </apply>
            <apply>
              <plus/>
              <apply>
                <power/>
                <ci> Ca_i </ci>
                <cn cellml:units="dimensionless"> 4.0 </cn>
              </apply>
              <apply>
                <power/>
                <ci> Kc </ci>
                <cn cellml:units="dimensionless"> 4.0 </cn>
              </apply>
            </apply>
          </apply>
          <ci> V_K </ci>
        </apply>
      </apply>
    </math>
  </component>  
  
  <component name="leak_current">
    <variable units="microA_per_cm2" public_interface="out" name="i_leak"/>
    
    <variable units="nanoS_per_millimolar" name="g_L" initial_value="0.09"/>        <variable units="millivolt" name="V_L" initial_value="-67.0"/>
   
    <variable units="second" public_interface="in" name="time"/>
    <variable units="millivolt" public_interface="in" name="V"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply id="i_leak_calculation">
        <eq/>
        <ci> i_leak </ci>
        <apply>
          <times/>
          <ci> g_L </ci>
          <apply>
            <minus/>
            <ci> V </ci>
            <ci> V_L </ci>
          </apply>
        </apply>
      </apply>
    </math>
  </component>
  
  <component name="ER_calcium">
    <variable units="millimolar" public_interface="out" name="Ca_er"/>
    <variable units="millimolar_per_millisecond" public_interface="out" name="J_rel"/>
    <variable units="millimolar_per_millisecond" public_interface="out" name="J_up"/>
    
    <variable units="picoL" name="V_er"/>
    <variable units="micromolar" name="K_er" initial_value="0.2"/>
    <variable units="dimensionless" name="f_er" initial_value="0.0025"/>
    <variable units="picoL_per_millisecond" name="P" initial_value="0.0012"/>
    <variable units="micromolar_picoL_per_millisecond" name="v_er" initial_value="0.05"/>
    
    <variable units="millimolar" public_interface="in" name="Ca_i"/>
    <variable units="picoL" public_interface="in" name="V_cell"/>
    <variable units="second" public_interface="in" name="time"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply id="Ca_er_diff_eq">
        <eq/>
        <apply>
          <diff/>
          <bvar>
            <ci> time </ci>
          </bvar>
          <ci> Ca_er </ci>
        </apply>
        <apply>
          <times/>
          <apply>
            <minus/>
            <apply>
              <divide/>
              <ci> f_er </ci>
              <ci> V_er </ci>
            </apply>
          </apply>
          <apply>
            <minus/>
            <ci> J_rel </ci>
            <ci> J_up </ci>
          </apply>
        </apply>
      </apply>
        
      <apply id="J_rel_calculation">
        <eq/>
        <ci> J_rel </ci>
        <apply>
          <times/>
          <ci> P </ci>
          <apply>
            <minus/>
            <ci> Ca_er </ci>
            <ci> Ca_i </ci>
          </apply>
        </apply>
      </apply>
      
      <apply id="J_up_calculation">
        <eq/>
        <ci> J_up </ci>
        <apply>
          <divide/>
          <apply>
            <times/>
            <ci> v_er </ci>
            <apply>
              <power/>
              <ci> Ca_i </ci>
              <cn cellml:units="dimensionless"> 2.0 </cn>
            </apply>
          </apply>
          <apply>
            <plus/>
            <apply>
              <power/>
              <ci> Ca_i </ci>
              <cn cellml:units="dimensionless"> 2.0 </cn>
            </apply>
            <apply>
              <power/>
              <ci> K_er </ci>
              <cn cellml:units="dimensionless"> 2.0 </cn>
            </apply>
          </apply>
        </apply>
      </apply>
      
      <apply id="V_er_calculation">
        <eq/>
        <ci> V_er </ci>
        <apply>
          <times/>
          <ci> V_cell </ci>
          <cn cellml:units="dimensionless"> 0.15 </cn>
        </apply>
      </apply>
    </math>
  </component>
  
  <component name="cytosolic_calcium">
    <variable units="millimolar" public_interface="out" name="Ca_i"/>
    
    <variable units="picoL" name="V_c"/>
    <variable units="micromolar" name="K_p" initial_value="0.08"/>
    <variable units="dimensionless" name="f_cyt" initial_value="0.01"/>
    <variable units="micromolar_micrometre_per_millisecond" name="v_p" initial_value="0.045"/>
    <variable units="millimolar_per_millisecond" name="J_in"/>
    <variable units="millimolar_per_millisecond" name="J_eff"/>
    <variable units="micromolar_micrometre_per_millisecond_per_picoA" name="alpha" initial_value="0.0074"/>
    <variable units="per_micrometre" name="beta" initial_value="0.47"/>
    
    <variable units="microA_per_cm2" public_interface="in" name="i_Ca_L"/>
    <variable units="microA_per_cm2" public_interface="in" name="i_Ca_T"/>
    <variable units="millimolar_per_millisecond" public_interface="in" name="J_rel"/>
    <variable units="millimolar_per_millisecond" public_interface="in" name="J_up"/>
    <variable units="picoL" public_interface="in" name="V_cell"/>
    <variable units="second" public_interface="in" name="time"/>
    
    <math xmlns="http://www.w3.org/1998/Math/MathML">
      <apply id="Ca_i_diff_eq">
        <eq/>
        <apply>
          <diff/>
          <bvar>
            <ci> time </ci>
          </bvar>
          <ci> Ca_i </ci>
        </apply>
        <apply>
          <plus/>
          <apply>
            <times/>
            <apply>
              <divide/>
              <ci> f_cyt </ci>
              <ci> V_c </ci>
            </apply>
            <apply>
              <minus/>
              <ci> J_rel </ci>
              <ci> J_up </ci>
            </apply>
          </apply>
          <apply>
            <times/>
            <ci> f_cyt </ci>
            <ci> beta </ci>
          </apply>
          <apply>
            <minus/>
            <ci> J_in </ci>
            <ci> J_eff </ci>
          </apply>
        </apply>
      </apply>
        
      <apply id="J_in_calculation">
        <eq/>
        <ci> J_in </ci>
        <apply>
          <times/>
          <apply>
            <minus/>
            <ci> alpha </ci>
          </apply>
          <apply>
            <plus/>
            <ci> i_Ca_L </ci>
            <ci> i_Ca_T </ci>
          </apply>
        </apply>
      </apply>
      
      <apply id="J_eff_calculation">
        <eq/>
        <ci> J_eff </ci>
        <apply>
          <divide/>
          <apply>
            <times/>
            <ci> v_p </ci>
            <apply>
              <power/>
              <ci> Ca_i </ci>
              <cn cellml:units="dimensionless"> 2.0 </cn>
            </apply>
          </apply>
          <apply>
            <plus/>
            <apply>
              <power/>
              <ci> Ca_i </ci>
              <cn cellml:units="dimensionless"> 2.0 </cn>
            </apply>
            <apply>
              <power/>
              <ci> K_p </ci>
              <cn cellml:units="dimensionless"> 2.0 </cn>
            </apply>
          </apply>
        </apply>
      </apply>
      
      <apply id="V_c_calculation">
        <eq/>
        <ci> V_c </ci>
        <apply>
          <times/>
          <ci> V_cell </ci>
          <cn cellml:units="dimensionless"> 0.85 </cn>
        </apply>
      </apply>
    </math>
  </component>
  
  <group>
    <relationship_ref relationship="containment"/>
    <component_ref component="membrane">
      <component_ref component="L_type_calcium_current">
        <component_ref component="L_type_calcium_current_m_gate"/>
      </component_ref>
      <component_ref component="T_type_calcium_current">
        <component_ref component="T_type_calcium_current_m_gate"/>
        <component_ref component="T_type_calcium_current_h_gate"/>
      </component_ref>
      <component_ref component="voltage_sensitive_K_current">
        <component_ref component="voltage_sensitive_K_current_n_gate"/>
      </component_ref>
      <component_ref component="Ca_activated_K_current"/>
      <component_ref component="leak_current"/>
      <component_ref component="ER_calcium"/>
      <component_ref component="cytosolic_calcium"/>
    </component_ref>
  </group>
  
  <group>
    <relationship_ref relationship="encapsulation"/>
    <component_ref component="L_type_calcium_current">
      <component_ref component="L_type_calcium_current_m_gate"/>
    </component_ref>
    <component_ref component="T_type_calcium_current">
      <component_ref component="T_type_calcium_current_m_gate"/>
      <component_ref component="T_type_calcium_current_h_gate"/>
    </component_ref>
    <component_ref component="voltage_sensitive_K_current">
      <component_ref component="voltage_sensitive_K_current_n_gate"/>
    </component_ref>
  </group>
  
  <connection>
    <map_components component_2="environment" component_1="membrane"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>

  <connection>
    <map_components component_2="environment" component_1="L_type_calcium_current"/>
    <map_variables variable_2="time" variable_1="time"/>
    <map_variables variable_2="Ca_e" variable_1="Ca_e"/>
    <map_variables variable_2="V_tau" variable_1="V_tau"/>
    <map_variables variable_2="k_tau" variable_1="k_tau"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="T_type_calcium_current"/>
    <map_variables variable_2="time" variable_1="time"/>
    <map_variables variable_2="V_tau" variable_1="V_tau"/>
    <map_variables variable_2="k_tau" variable_1="k_tau"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="voltage_sensitive_K_current"/>
    <map_variables variable_2="time" variable_1="time"/>
    <map_variables variable_2="K_e" variable_1="K_e"/>
    <map_variables variable_2="K_i" variable_1="K_i"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="Ca_activated_K_current"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="leak_current"/>
    <map_variables variable_2="time" variable_1="time"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="ER_calcium"/>
    <map_variables variable_2="time" variable_1="time"/>
    <map_variables variable_2="V_cell" variable_1="V_cell"/>
  </connection>
  
  <connection>
    <map_components component_2="environment" component_1="cytosolic_calcium"/>
    <map_variables variable_2="time" variable_1="time"/>
    <map_variables variable_2="V_cell" variable_1="V_cell"/>
  </connection>
  
  <connection>
    <map_components component_2="L_type_calcium_current" component_1="membrane"/>
    <map_variables variable_2="V" variable_1="V"/>
    <map_variables variable_2="i_Ca_L" variable_1="i_Ca_L"/>
    <map_variables variable_2="R" variable_1="R"/>
    <map_variables variable_2="F" variable_1="F"/>
    <map_variables variable_2="T" variable_1="T"/>
  </connection> 
  
  <connection>
    <map_components component_2="T_type_calcium_current" component_1="membrane"/>
    <map_variables variable_2="V" variable_1="V"/>
    <map_variables variable_2="i_Ca_T" variable_1="i_Ca_T"/>
  </connection> 
  
  <connection>
    <map_components component_2="voltage_sensitive_K_current" component_1="membrane"/>
    <map_variables variable_2="V" variable_1="V"/>
    <map_variables variable_2="i_K_DR" variable_1="i_K_DR"/>
    <map_variables variable_2="R" variable_1="R"/>
    <map_variables variable_2="F" variable_1="F"/>
    <map_variables variable_2="T" variable_1="T"/>
  </connection>
  
  <connection>
    <map_components component_2="Ca_activated_K_current" component_1="membrane"/>
    <map_variables variable_2="V" variable_1="V"/>
    <map_variables variable_2="i_K_Ca" variable_1="i_K_Ca"/>
  </connection> 
  
  <connection>
    <map_components component_2="leak_current" component_1="membrane"/>
    <map_variables variable_2="V" variable_1="V"/>
    <map_variables variable_2="i_leak" variable_1="i_leak"/>
  </connection>
  
  <connection>
    <map_components component_2="T_type_calcium_current" component_1="L_type_calcium_current"/>
    <map_variables variable_2="V_Ca" variable_1="V_Ca"/>
  </connection>
  
  <connection>
    <map_components component_2="cytosolic_calcium" component_1="L_type_calcium_current"/>
    <map_variables variable_2="Ca_i" variable_1="Ca_i"/>
    <map_variables variable_2="i_Ca_L" variable_1="i_Ca_L"/>
  </connection>
  
  <connection>
    <map_components component_2="cytosolic_calcium" component_1="T_type_calcium_current"/>
    <map_variables variable_2="i_Ca_T" variable_1="i_Ca_T"/>
  </connection>
  
  <connection>
    <map_components component_2="Ca_activated_K_current" component_1="voltage_sensitive_K_current"/>
    <map_variables variable_2="V_K" variable_1="V_K"/>
  </connection>
  
  <connection>
    <map_components component_2="cytosolic_calcium" component_1="Ca_activated_K_current"/>
    <map_variables variable_2="Ca_i" variable_1="Ca_i"/>
  </connection>
  
  <connection>
    <map_components component_2="cytosolic_calcium" component_1="ER_calcium"/>
    <map_variables variable_2="Ca_i" variable_1="Ca_i"/>
    <map_variables variable_2="J_rel" variable_1="J_rel"/>
    <map_variables variable_2="J_up" variable_1="J_up"/>
  </connection>
        
  <connection>
    <map_components component_2="L_type_calcium_current_m_gate" component_1="L_type_calcium_current"/>
    <map_variables variable_2="m_L" variable_1="m_L"/>
    <map_variables variable_2="time" variable_1="time"/>
    <map_variables variable_2="V" variable_1="V"/>
    <map_variables variable_2="V_tau" variable_1="V_tau"/>
    <map_variables variable_2="k_tau" variable_1="k_tau"/>
  </connection>
  
  <connection>
    <map_components component_2="T_type_calcium_current_m_gate" component_1="T_type_calcium_current"/>
    <map_variables variable_2="m_T" variable_1="m_T"/>
    <map_variables variable_2="time" variable_1="time"/>
    <map_variables variable_2="V" variable_1="V"/>
    <map_variables variable_2="V_tau" variable_1="V_tau"/>
    <map_variables variable_2="k_tau" variable_1="k_tau"/>
  </connection>
  
  <connection>
    <map_components component_2="T_type_calcium_current_h_gate" component_1="T_type_calcium_current"/>
    <map_variables variable_2="h_T" variable_1="h_T"/>
    <map_variables variable_2="time" variable_1="time"/>
    <map_variables variable_2="V" variable_1="V"/>
  </connection>
  
  <connection>
    <map_components component_2="voltage_sensitive_K_current_n_gate" component_1="voltage_sensitive_K_current"/>
    <map_variables variable_2="n" variable_1="n"/>
    <map_variables variable_2="time" variable_1="time"/>
    <map_variables variable_2="V" variable_1="V"/>
  </connection>


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    <vCard:Given>Catherine</vCard:Given>
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         Shorten and Wall's 2000 Hodgkin-Huxley type mathematical model of 
         bursting oscillations in pituitary corticotrophs. 
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    <cmeta:bio_entity>Pituitary Corticotrophs</cmeta:bio_entity>
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        The University of Auckland, Bioengineering Institute
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    <dc:title>Bulletin of Mathematical Biology</dc:title>
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          This is the CellML description of Shorten and Wall's 2000 
          Hodgkin-Huxley type mathematical model of bursting oscillations in 
          pituitary corticotrophs. 
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    <vCard:Given>David</vCard:Given>
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            A Hodgkin-Huxley Model Exhibiting Bursting Oscillations
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    <bqs:volume>62</bqs:volume>
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