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        <div class="dc:title">Smith2009 - RGS mediated GTP hydrolysis</div>
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          <p>This model is described in the article:</p>
          <div class="bibo:title">
            <a href="http://identifiers.org/pubmed/19285552" title="Access to this publication">Dual positive and negative regulation of GPCR signaling by GTP hydrolysis.</a>
          </div>
          <div class="bibo:authorList">Smith B, Hill C, Godfrey EL, Rand D, van den Berg H, Thornton S, Hodgkin M, Davey J, Ladds G.</div>
          <div class="bibo:Journal">Cell Signal. 2009 Jul;21(7):1151-60.</div>
          <p>Abstract:</p>
          <div class="bibo:abstract">
            <p>G protein-coupled receptors (GPCRs) regulate a variety of intracellular pathways through their ability to promote the binding of GTP to heterotrimeric G proteins. Regulator of G protein signaling (RGS) proteins increases the intrinsic GTPase activity of Galpha-subunits and are widely regarded as negative regulators of G protein signaling. Using yeast we demonstrate that GTP hydrolysis is not only required for desensitization, but is essential for achieving a high maximal (saturated level) response. Thus RGS-mediated GTP hydrolysis acts as both a negative (low stimulation) and positive (high stimulation) regulator of signaling. To account for this we generated a new kinetic model of the G protein cycle where Galpha(GTP) enters an inactive GTP-bound state following effector activation. Furthermore, in vivo and in silico experimentation demonstrates that maximum signaling output first increases and then decreases with RGS concentration. This unimodal, non-monotone dependence on RGS concentration is novel. Analysis of the kinetic model has revealed a dynamic network motif that shows precisely how inclusion of the inactive GTP-bound state for the Galpha produces this unimodal relationship.</p>
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          <p>To reproduce dose-response plots in the publication, the model is simulated with 12 different concentrations (see parameter Ligand_conc). For each concentration, a single value must be obtained from the integral of the trajectory of species z3 from time=0 to time=30. These values are then used to build a dose-response plot (authors used GraphPad Prism). Mutant strains are simulated with alternative parameter values or initial conditions in Table S3.</p>
        </div>
        <div class="dc:publisher">
          <p>This model is hosted on        <a href="http://www.ebi.ac.uk/biomodels">BioModels Database</a>
            and identified by:        <a href="http://www.ebi.ac.uk/biomodels/MODEL1212040001">MODEL1212040001</a>
            .        </p>
          <p>To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. PMID:        <a href="http://identifiers.org/pubmed/20587024">20587024</a>
            .        </p>
        </div>
        <div class="dc:license">
          <p>To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to the public
domain worldwide. Please refer to        <a href="http://creativecommons.org/publicdomain/zero/1.0/" title="Access to: CC0 1.0 Universal (CC0 1.0), Public Domain Dedication">CC0 Public Domain
Dedication</a>
            for more information.        </p>
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                <rdf:Bag>
                  <rdf:li rdf:resource="http://identifiers.org/sbo/SBO:0000347"/>
                </rdf:Bag>
              </bqbiol:isVersionOf>
            </rdf:Description>
          </rdf:RDF>
        </annotation>
      </species>
      <species metaid="_477188" id="z3" name="z3" compartment="compartment" initialConcentration="0" substanceUnits="nanomole">
        <annotation>
          <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/">
            <rdf:Description rdf:about="#_477188">
              <bqbiol:isVersionOf>
                <rdf:Bag>
                  <rdf:li rdf:resource="http://identifiers.org/sbo/SBO:0000347"/>
                </rdf:Bag>
              </bqbiol:isVersionOf>
            </rdf:Description>
          </rdf:RDF>
        </annotation>
      </species>
    </listOfSpecies>
    <listOfParameters>
      <parameter metaid="_477200" id="ka" name="ka" value="1.5" units="FirstOrder" constant="true"/>
      <parameter metaid="_477212" id="Ligand_conc" name="Ligand_conc" value="0.1" units="nanoMolar" constant="true">
        <notes>
          <p xmlns="http://www.w3.org/1999/xhtml">
        Dose-response plots use: 0.1, 1, 3.16228, 10, 31.6228, 100, 316.228, 1000, 3162.28, 10000, 31622.8, 100000</p>
        </notes>
      </parameter>
    </listOfParameters>
    <listOfReactions>
      <reaction metaid="_477224" sboTerm="SBO:0000526" id="R1" name="Receptor-Ligand association" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_477236" species="R"/>
          <speciesReference metaid="_477249" species="L"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_477261" species="RL"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114157" species="R"/>
          <modifierSpeciesReference metaid="_114169" species="L"/>
        </listOfModifiers>
        <kineticLaw metaid="_477273">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> R </ci>
              <ci> L </ci>
              <ci> k1 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_477285" id="k1" name="k1" value="0.0025" units="SecondOrder">
              <notes>
                <p xmlns="http://www.w3.org/1999/xhtml">
              The value of this parameter in the original publication is incorrect. It has been corrected in agreement with the authors.</p>
              </notes>
            </parameter>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_477297" sboTerm="SBO:0000526" id="R2" name="Receptor-Gprotein association" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_477310" species="R"/>
          <speciesReference metaid="_477323" species="Gabg"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_477335" species="RGabg"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114181" species="R"/>
          <modifierSpeciesReference metaid="_114193" species="Gabg"/>
        </listOfModifiers>
        <kineticLaw metaid="_477347">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> R </ci>
              <ci> Gabg </ci>
              <ci> k2 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_477359" id="k2" name="k2" value="0.005" units="SecondOrder">
              <notes>
                <p xmlns="http://www.w3.org/1999/xhtml">
              The value of this parameter in the original publication is incorrect. It has been corrected in agreement with the authors.</p>
              </notes>
            </parameter>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_477371" sboTerm="SBO:0000526" id="R3" name="RL-Gprotein association" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_477383" species="RL"/>
          <speciesReference metaid="_477395" species="Gabg"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_477407" species="RGabgL"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114205" species="RL"/>
          <modifierSpeciesReference metaid="_114217" species="Gabg"/>
        </listOfModifiers>
        <kineticLaw metaid="_477419">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> RL </ci>
              <ci> Gabg </ci>
              <ci> k3 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_477431" id="k3" name="k3" value="0.02" units="SecondOrder"/>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_477443" sboTerm="SBO:0000526" id="R4" name="RGabg-Ligand association" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_477455" species="RGabg"/>
          <speciesReference metaid="_477467" species="L"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_477479" species="RGabgL"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114229" species="RGabg"/>
          <modifierSpeciesReference metaid="_114241" species="L"/>
        </listOfModifiers>
        <kineticLaw metaid="_477491">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> RGabg </ci>
              <ci> L </ci>
              <ci> k4 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_477504" id="k4" name="k4" value="0.005" units="SecondOrder">
              <notes>
                <p xmlns="http://www.w3.org/1999/xhtml">
              The value of this parameter in the original publication is incorrect. It has been corrected in agreement with the authors.</p>
              </notes>
            </parameter>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_477516" id="R5" name="Galpha activation by receptor" reversible="false" fast="false">
        <annotation>
          <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/">
            <rdf:Description rdf:about="#_477516">
              <bqbiol:isVersionOf>
                <rdf:Bag>
                  <rdf:li rdf:resource="http://identifiers.org/go/GO:0004872"/>
                </rdf:Bag>
              </bqbiol:isVersionOf>
            </rdf:Description>
          </rdf:RDF>
        </annotation>
        <listOfReactants>
          <speciesReference metaid="_477528" species="RGabgL"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_477540" species="RL"/>
          <speciesReference metaid="_477552" species="GaGTP"/>
          <speciesReference metaid="_477564" species="Gbg"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114253" species="RGabgL"/>
        </listOfModifiers>
        <kineticLaw metaid="_477576">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> RGabgL </ci>
              <ci> k5 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_477588" id="k5" name="k5" value="50" units="FirstOrder"/>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_477601" id="R6" name="Galpha activation spontaneous" reversible="false" fast="false">
        <annotation>
          <rdf:RDF xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:bqbiol="http://biomodels.net/biology-qualifiers/">
            <rdf:Description rdf:about="#_477601">
              <bqbiol:isVersionOf>
                <rdf:Bag>
                  <rdf:li rdf:resource="http://identifiers.org/go/GO:0004872"/>
                </rdf:Bag>
              </bqbiol:isVersionOf>
            </rdf:Description>
          </rdf:RDF>
        </annotation>
        <listOfReactants>
          <speciesReference metaid="_477613" species="Gabg"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_477625" species="GaGTP"/>
          <speciesReference metaid="_477637" species="Gbg"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114265" species="Gabg"/>
        </listOfModifiers>
        <kineticLaw metaid="_477649">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> Gabg </ci>
              <ci> k6 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_477661" id="k6" name="k6" value="0.2" units="FirstOrder">
              <notes>
                <p xmlns="http://www.w3.org/1999/xhtml">
              The value of this parameter in the original publication is incorrect. It has been corrected in agreement with the authors.</p>
              </notes>
            </parameter>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_477673" sboTerm="SBO:0000526" id="R7" name="Galpha-RGS association" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_477685" species="GaGTP"/>
          <speciesReference metaid="_477697" species="RGS"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_477709" species="RGSGaGTP"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114277" species="GaGTP"/>
          <modifierSpeciesReference metaid="_114289" species="RGS"/>
        </listOfModifiers>
        <kineticLaw metaid="_477721">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> GaGTP </ci>
              <ci> RGS </ci>
              <ci> k7 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_477733" id="k7" name="k7" value="500" units="SecondOrder"/>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_477745" sboTerm="SBO:0000169" id="R8" name="Galpha deactivation by RGS" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_477757" species="RGSGaGTP"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_477769" species="GaGDPP"/>
          <speciesReference metaid="_477781" species="RGS"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114301" species="RGSGaGTP"/>
        </listOfModifiers>
        <kineticLaw metaid="_477793">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> RGSGaGTP </ci>
              <ci> k8 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_477805" id="k8" name="k8" value="2.5" units="FirstOrder"/>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_477817" sboTerm="SBO:0000169" id="R9" name="Galpha deactivation spontaneous" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_477829" species="GaGTP"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_477841" species="GaGDPP"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114313" species="GaGTP"/>
        </listOfModifiers>
        <kineticLaw metaid="_477853">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> GaGTP </ci>
              <ci> k9 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_477865" id="k9" name="k9" value="0.005" units="FirstOrder"/>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_477877" sboTerm="SBO:0000526" id="R10" name="Galpha-Effector association" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_477890" species="Effector"/>
          <speciesReference metaid="_477902" species="GaGTP"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_477914" species="GaGTPEffector"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114325" species="Effector"/>
          <modifierSpeciesReference metaid="_114337" species="GaGTP"/>
        </listOfModifiers>
        <kineticLaw metaid="_477927">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> Effector </ci>
              <ci> GaGTP </ci>
              <ci> k10 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_477939" id="k10" name="k10" value="10" units="SecondOrder"/>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_477951" sboTerm="SBO:0000169" id="R11" name="Galpha becomes inert" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_477963" species="GaGTPEffector"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_477975" species="inertGaGTP"/>
          <speciesReference metaid="_477987" species="Effector"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114349" species="GaGTPEffector"/>
        </listOfModifiers>
        <kineticLaw metaid="_477999">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> GaGTPEffector </ci>
              <ci> k11 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_478011" id="k11" name="k11" value="1" units="FirstOrder">
              <notes>
                <p xmlns="http://www.w3.org/1999/xhtml">
              The value of this parameter in the original publication is incorrect. It has been corrected in agreement with the authors.</p>
              </notes>
            </parameter>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_478023" sboTerm="SBO:0000526" id="R12" name="inertGalpha-RGS association" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_478035" species="inertGaGTP"/>
          <speciesReference metaid="_478047" species="RGS"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_478059" species="RGSinertGaGTP"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114361" species="inertGaGTP"/>
          <modifierSpeciesReference metaid="_114373" species="RGS"/>
        </listOfModifiers>
        <kineticLaw metaid="_478072">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> inertGaGTP </ci>
              <ci> RGS </ci>
              <ci> k12 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_478084" id="k12" name="k12" value="50" units="SecondOrder"/>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_478096" sboTerm="SBO:0000169" id="R13" name="inertGalpha deactivation by RGS" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_478108" species="RGSinertGaGTP"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_478120" species="GaGDPP"/>
          <speciesReference metaid="_478132" species="RGS"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114385" species="RGSinertGaGTP"/>
        </listOfModifiers>
        <kineticLaw metaid="_478144">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> RGSinertGaGTP </ci>
              <ci> k13 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_478156" id="k13" name="k13" value="0.3" units="FirstOrder"/>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_478169" sboTerm="SBO:0000169" id="R14" name="inertGalpha deactivation spontaneous" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_478181" species="inertGaGTP"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_478193" species="GaGDPP"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114397" species="inertGaGTP"/>
        </listOfModifiers>
        <kineticLaw metaid="_478205">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> inertGaGTP </ci>
              <ci> k14 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_478217" id="k14" name="k14" value="0.005" units="FirstOrder"/>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_478230" sboTerm="SBO:0000393" id="R15" name="Phosphate release" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_478242" species="GaGDPP"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_478254" species="GaGDP"/>
          <speciesReference metaid="_478266" species="P"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114409" species="GaGDPP"/>
        </listOfModifiers>
        <kineticLaw metaid="_478278">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> GaGDPP </ci>
              <ci> k15 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_478290" id="k15" name="k15" value="1000" units="FirstOrder"/>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_478302" sboTerm="SBO:0000526" id="R16" name="Gprotein subunits association" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_478315" species="GaGDP"/>
          <speciesReference metaid="_478327" species="Gbg"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_478339" species="Gabg"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114421" species="GaGDP"/>
          <modifierSpeciesReference metaid="_114433" species="Gbg"/>
        </listOfModifiers>
        <kineticLaw metaid="_478351">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> GaGDP </ci>
              <ci> Gbg </ci>
              <ci> k16 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_478363" id="k16" name="k16" value="1000" units="SecondOrder"/>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_478375" sboTerm="SBO:0000179" id="R17" name="Phosphate degradation" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_478387" species="P"/>
        </listOfReactants>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114445" species="P"/>
        </listOfModifiers>
        <kineticLaw metaid="_478399">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> P </ci>
              <ci> k17 </ci>
            </apply>
          </math>
          <listOfParameters>
            <parameter metaid="_478411" id="k17" name="k17" value="10" units="FirstOrder"/>
          </listOfParameters>
        </kineticLaw>
      </reaction>
      <reaction metaid="_478423" sboTerm="SBO:0000225" id="R18" name="Delay 1" reversible="false" fast="false">
        <listOfProducts>
          <speciesReference metaid="_478435" species="z1"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_478447" species="GaGTPEffector"/>
          <modifierSpeciesReference metaid="_114457" species="GaGTPEffector"/>
        </listOfModifiers>
        <kineticLaw metaid="_478459">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> GaGTPEffector </ci>
              <ci> ka </ci>
            </apply>
          </math>
        </kineticLaw>
      </reaction>
      <reaction metaid="_478472" sboTerm="SBO:0000225" id="R19" name="Delay 2" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_478484" species="z1"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_478496" species="z2"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114470" species="z1"/>
        </listOfModifiers>
        <kineticLaw metaid="_478508">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> z1 </ci>
              <ci> ka </ci>
            </apply>
          </math>
        </kineticLaw>
      </reaction>
      <reaction metaid="_478520" sboTerm="SBO:0000225" id="R20" name="Delay 3" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_478532" species="z2"/>
        </listOfReactants>
        <listOfProducts>
          <speciesReference metaid="_478545" species="z3"/>
        </listOfProducts>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114482" species="z2"/>
        </listOfModifiers>
        <kineticLaw metaid="_478557">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> z2 </ci>
              <ci> ka </ci>
            </apply>
          </math>
        </kineticLaw>
      </reaction>
      <reaction metaid="_478569" sboTerm="SBO:0000225" id="R21" name="Delay 4" reversible="false" fast="false">
        <listOfReactants>
          <speciesReference metaid="_478581" species="z3"/>
        </listOfReactants>
        <listOfModifiers>
          <modifierSpeciesReference metaid="_114494" species="z3"/>
        </listOfModifiers>
        <kineticLaw metaid="_478594">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <times/>
              <ci> compartment </ci>
              <ci> z3 </ci>
              <ci> ka </ci>
            </apply>
          </math>
        </kineticLaw>
      </reaction>
    </listOfReactions>
    <listOfEvents>
      <event metaid="_478606" id="Ligand_addition" name="Ligand_addition" useValuesFromTriggerTime="true">
        <notes>
          <p xmlns="http://www.w3.org/1999/xhtml">
        The model in the publication uses a tanh step function to add ligand, but only because the solver used by the authors did not support Events. Results are identical using this event, and has been changed in agreement with the authors.</p>
        </notes>
        <trigger metaid="_478618">
          <math xmlns="http://www.w3.org/1998/Math/MathML">
            <apply>
              <geq/>
              <csymbol encoding="text" definitionURL="http://www.sbml.org/sbml/symbols/time"> time </csymbol>
              <cn type="integer"> 14 </cn>
            </apply>
          </math>
        </trigger>
        <listOfEventAssignments>
          <eventAssignment metaid="_478630" variable="L">
            <math xmlns="http://www.w3.org/1998/Math/MathML">
              <apply>
                <plus/>
                <ci> L </ci>
                <ci> Ligand_conc </ci>
              </apply>
            </math>
          </eventAssignment>
        </listOfEventAssignments>
      </event>
    </listOfEvents>
  </model>
</sbml>
