Gq coupled signaling pathways involved in striatal synaptic plasticity (Kim et al. 2013)

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Accession:154967
Model of Gq coupled signaling pathways underlying synaptic plasticity in striatal medium spiny projection neurons. Reactions and diffusion are implemented stochastically in a dendrite with one or more diffusionally coupled spines. Simulations demonstrate that theta burst stimulation, which produces LTP, increases the ratio of PKC:2AG as compared to 20 Hz stimulation, which produces LTD.
Reference:
1 . Kim B, Hawes SL, Gillani F, Wallace LJ, Blackwell KT (2013) Signaling pathways involved in striatal synaptic plasticity are sensitive to temporal pattern and exhibit spatial specificity. PLoS Comput Biol 9:e1002953 [PubMed]
Citations  Citation Browser
Model Information (Click on a link to find other models with that property)
Model Type: Molecular Network;
Brain Region(s)/Organism:
Cell Type(s): Neostriatum medium spiny direct pathway GABA cell;
Channel(s):
Gap Junctions:
Receptor(s): mGluR1;
Gene(s):
Transmitter(s):
Simulation Environment: NeuroRD;
Model Concept(s): Synaptic Plasticity; Signaling pathways;
Implementer(s): Blackwell, Avrama [avrama at gmu.edu];
Search NeuronDB for information about:  Neostriatum medium spiny direct pathway GABA cell; mGluR1;
<ReactionScheme>
<!-- changes by AB: 
   1. changed variable names, such as Q to G
   2. Suggested reactions for more realistic (and partly depleting) PIP2 regen
   3. Comment that we need DAG degradation -->

<!-- changes on 110923:
   1. removed Mpep molecules and reactions (not used) and CaB (not used)
   2. Added DAG conversion to PA
-->
<!-- changes on Nov 29, 2011:
Elminate Q term, now have true regeneration of Pip2 from Ip3 degrad
-->
<!-- changes on Nov 30, 2011:
1. Decrease rate of PLC binding to Ca by 5x (keep same affinity)
2. Decrease rate of PlcCa binding to GaGTP (keep affinity)
3. Decrease rate of PlcCa hydrolysis of Pip2 by 5x (producing way too much Ip3 basal)
4. Decrease rate of PlcCaGaGTP hydrolysis by 2x (keep GaGTP accelerates PLC by 10x)
5. Increase rate of PIkinase activity by 10x (too high Ip3deg is building up) 
-->
<!-- changes on Dec 2, 2011:
A: mglu_2ag_reac11dec2pikinase10x.xml
1. decrease  degradation rate of Ip3 (to increase conc) and 2ag
2. halve affinity and binding rate of Dgl for Ca
B: mglu_2ag_reac11dec2plcSlow.xml
Slow down PLC even more by increasing kb 5x.
-->
<!-- Changes on Dec 8, 2011:
1. speed up PIkinase degradation even more
2. lower speed and affinity of Dag lipase for DAG
-->
<!-- changese on Dec 16, 2011:
1. Ca binds Cam on either site first 
-->
<!-- changes on Dec 20, 2011:
1. halve the 2ag degrad
2. Slowing down Dgl activity by 4x to help the saturation
-->
<!-- changes on Jan 4, 2012:
1. lower affinity of Dag lipase (mistakenly raised it on Dec 8, 2011)
-->
<!-- Mglu agonist and antagonist reactions leading to IP3, DAG, and 2AG production-->
<!-- changes on Jan 31, 2012:
1. lower affinity of Dag lipase for calcium -->
<!-- Changes on Feb 15, 2011
Many previous attemps at more Gap activity didn't work
Let's try lower affinity of Plc for GaGTP, since current values not based on data -->
<!-- Changes on Feb 17, 2012
1. Desensitization of DhpgMglu - need to decrease rate of GaGTP production
2. True Gap activity - moderate rate of regeneration of Gabg from GaGDP - does Gabg deplete at all?-->
<!--Changes on Feb 22, 2012
1. Gap activity of PlcCaGaGTP 
2. spont hydrolysis of GaGTP
Note that GaGTP has higher quantity, but slower hydrolysis than PlcCaGaGTP -->
<!-- Changes on Mar5, 2012
less desensitization of DhpgMglu - can be weaker since Gabg is lower -->
<!--changes on Mar 20, 2012
even less desensitization to match even lower Gabg -->

    <Specie name="Dhpg"          id="Dhpg"          kdiff="100"    kdiffunit = "mu2/s"/>
    <Specie name="DhpgMglu"      id="DhpgMglu"      kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="Mglu"          id="Mglu"          kdiff="0"    kdiffunit = "mu2/s"/>

    <Specie name="DhpgMgluDesen" id="DhpgMgluDesen" kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="DhpgOut"       id="DhpgOut"          kdiff="100"    kdiffunit = "mu2/s"/>

    <Specie name="Gabg"           id="Gabg"           kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="GabgDhpgMglu"   id="GabgDhpgMglu"   kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="GaGTP"          id="GaGTP"           kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="GaGDP"          id="GaGDP"           kdiff="0"    kdiffunit = "mu2/s"/>

    <Specie name="Ca"            id="Ca"            kdiff="174.3"   kdiffunit="mu2/s"/>
    <Specie name="CaOut"         id="CaOut"         kdiff="174.3"   kdiffunit="mu2/s"/>
    <Specie name="CaOutLeak"     id="CaOutLeak"     kdiff="0"       kdiffunit="mu2/s"/>
    <Specie name="Leak"          id="Leak"          kdiff="0"       kdiffunit="mu2/s"/>
    <Specie name="Calbin"        id="Calbin"        kdiff="9.3"     kdiffunit="mu2/s"/>
    <Specie name="CalbinC"       id="CalbinC"       kdiff="9.3"     kdiffunit="mu2/s"/>
    
    <Specie name="pmca" id="pmca" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="ncx" id="ncx" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="pmcaCa" id="pmcaCa" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="ncxCa" id="ncxCa" kdiff="0" kdiffunit="mu2/s"/>
    
    <Specie name="CaM" id="CaM" kdiff="11" kdiffunit="mu2/s"/>
    <Specie name="CaMCa2C" id="CaMCa2C" kdiff="11" kdiffunit="mu2/s"/>
    <Specie name="CaMCa2N" id="CaMCa2N" kdiff="11" kdiffunit="mu2/s"/>
    <Specie name="CaMCa4" id="CaMCa4" kdiff="11" kdiffunit="mu2/s"/>
     
    <Specie name="Plc"            id="Plc"           kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="PlcCa"          id="PlcCa"         kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="PlcCaGaGTP"      id="PlcCaGaGTP"      kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="PlcGaGTP"        id="PlcGaGTP"        kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="Pip2"            id="Pip2"            kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="PlcCaPip2"       id="PlcCaPip2"       kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="PlcCaGaGTPPip2"  id="PlcCaGaGTPPip2"    kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="Ip3"             id="Ip3"           kdiff="10.6"    kdiffunit = "mu2/s"/>
    <Specie name="PlcCaDag"        id="PlcCaDag"      kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="PlcCaGaGTPDag"   id="PlcCaGaGTPDag"   kdiff="0"    kdiffunit = "mu2/s"/>
    
    <Specie name="PIkinase"      id="PIkinase"      kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="Ip3degPIk"     id="Ip3degPIk"   kdiff="0"    kdiffunit = "mu2/s"/>
    
    <Specie name="Pkc"           id="Pkc"   kdiff="14"    kdiffunit = "mu2/s"/>
    <Specie name="PkcCa"         id="PkcCa"   kdiff="14"    kdiffunit = "mu2/s"/>
    <Specie name="Pkct"          id="Pkct"   kdiff="0"    kdiffunit = "mu2/s"/>
   
    <Specie name="Dag"           id="Dag"           kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="DagK"          id="DagK"          kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="DagKdag"       id="DagKdag"      kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="PA"            id="PA"           kdiff="0"    kdiffunit = "mu2/s"/>

    <Specie name="Dgl"           id="Dgl"           kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="CaDgl"         id="CaDgl"         kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="DagCaDgl"      id="DagCaDgl"      kdiff="0"    kdiffunit = "mu2/s"/>
    <Specie name="2ag"           id="2ag"           kdiff="88.6"    kdiffunit = "mu2/s"/>

    <Specie name="2agDegrad"       id="2agDegrad"           kdiff="88.6"    kdiffunit = "mu2/s"/>
    <Specie name="Ip3degrad"       id="Ip3degrad"           kdiff="10.6"    kdiffunit = "mu2/s"/>


<!-- Ca pump high affinity -    Ca + pmca <-> pmcaCa -->
    <Reaction name = "Ca_pump1a" id="Ca_pump1a">
	<Reactant specieID="Ca"/>
	<Reactant specieID="pmca"/>
	<Product specieID="pmcaCa"/>

	<forwardRate>0.5e-4</forwardRate>
	<reverseRate>0.007</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!-- Ca pump high affinity -    pmcaCa <-> pmca + CaOut -->
    <Reaction name = "Ca_pump1b" id="Ca_pump1b">
	<Reactant specieID="pmcaCa"/>
	<Product specieID="pmca"/>
	<Product specieID="CaOut"/>

	<forwardRate>0.0035</forwardRate>
	<reverseRate>0</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!-- Ca pump low affinity -    Ca + ncx <-> ncxCa -->
    <Reaction name = "Ca_pump2a" id="Ca_pump2a">
	<Reactant specieID="Ca"/>
	<Reactant specieID="ncx"/>
	<Product specieID="ncxCa"/>

	<forwardRate>1.68e-5</forwardRate>
	<reverseRate>0.0112</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!-- Ca pump low affinity -    ncxCa <-> ncx + CaOut -->
    <Reaction name = "Ca_pump2b" id="Ca_pump2b">
	<Reactant specieID="ncxCa"/>
	<Product specieID="ncx"/>
	<Product specieID="CaOut"/>

	<forwardRate>0.0056</forwardRate>
	<reverseRate>0</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!-- Ca leak -    CaOut + Leak <-> CaOutLeak -->
    <Reaction name = "Ca_leak" id="Ca_leak">
	<Reactant specieID="CaOut"/>
	<Reactant specieID="Leak"/>
	<Product specieID="CaOutLeak"/>

        <forwardRate>1.5e-6</forwardRate>
	<reverseRate>1.1e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!-- Ca leak -    CaOutLeak <-> Ca (inside) + Leak  -->
    <Reaction name = "Ca_leak" id="Ca_leak">
	<Reactant specieID="CaOutLeak"/>
	<Product specieID="Ca"/>
	<Product specieID="Leak"/>

        <forwardRate>1.1e-3</forwardRate>
	<reverseRate>0</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!-- Ca Buffer    Ca + Calbindin <-> calbinCa -->
    <Reaction name = "Ca_buffer" id="Ca_Buffer">
        <Reactant specieID="Ca"/>
        <Reactant specieID="Calbin"/>
        <Product specieID="CalbinC"/>

        <forwardRate>2.8e-5</forwardRate>
        <reverseRate>0.0196</reverseRate>
        <Q10>0.2</Q10>
    </Reaction>


<!--1) CaM  + 2Ca <-> CaMCa2C -->
    <Reaction name = "CaMC_bind" id="CaMC_bind">
	<Reactant specieID="CaM"/>
	<Reactant specieID="Ca" n="2"/>
	<Product specieID="CaMCa2C"/>

	<forwardRate>6e-6</forwardRate>
	<reverseRate>9.1e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!--2) CaMCa2C  + 2Ca <-> CaMCa4 -->
    <Reaction name = "CaMCa2C_bind" id="CaMCa2C_bind">
	<Reactant specieID="CaMCa2C"/>
	<Reactant specieID="Ca" n="2"/>
	<Product specieID="CaMCa4"/>

	<forwardRate>0.1e-3</forwardRate>
	<reverseRate>1000e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!--1) CaM  + 2Ca <-> CaMCa2N -->
    <Reaction name = "CaMN_bind" id="CaMN_bind">
	<Reactant specieID="CaM"/>
	<Reactant specieID="Ca" n="2"/>
	<Product specieID="CaMCa2N"/>

	<forwardRate>0.1e-3</forwardRate>
	<reverseRate>1000e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!--2) CaMCa2N  + 2Ca <-> CaMCa4 -->
    <Reaction name = "CaMCa2N_bind" id="CaMCa2N_bind">
	<Reactant specieID="CaMCa2N"/>
	<Reactant specieID="Ca" n="2"/>
	<Product specieID="CaMCa4"/>

	<forwardRate>6e-6</forwardRate>
	<reverseRate>9.1e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>



   <!-- DhpgOut    Dhpg <-> DhpgOut>  -->
  <Reaction name = "Dhpg--DhpgOut" id="Dhpg--DhpgOut">
  	<Reactant specieID="Dhpg"/>
	  <Product specieID="DhpgOut"/>

  	<forwardRate>2e-3</forwardRate>
  	<reverseRate>2e-8</reverseRate>
  	<Q10>0.2</Q10>
  </Reaction>
  



   <!-- Dhpg + Mglu <==> DhpgMglu  -->
      <Reaction name = "Dhpg+Mglu--DhpgMglu" id="Dhpg+Mglu--DhpgMglu">
        <Reactant specieID="Dhpg"              />
        <Reactant specieID="Mglu"              />
        <Product  specieID="DhpgMglu"         />

        <forwardRate> 0.1e-06 </forwardRate>
        <reverseRate> 10e-03      </reverseRate>
        <Q10>         0.2          </Q10>
    </Reaction>

   <!-- DhpgMglu <==> Desensitized -->
      <Reaction name = "Dhpg+Mglu--DhpgMglu" id="Dhpg+Mglu--DhpgMglu">
        <Reactant specieID="DhpgMglu"              />
        <Product  specieID="DhpgMgluDesen"         />

        <forwardRate> 0.25e-03 </forwardRate>
        <reverseRate> 1e-06      </reverseRate>
        <Q10>         0.2          </Q10>
    </Reaction>

   <!-- Gabg + DhpgMglu    <-> GabgDhpgMglu    -->
    <Reaction name = "Gabg+DhpgMglu--GabgDhpgMglu" id="Gabg+DhpgMglu--GabgDhpgMglu">
        <Reactant specieID="Gabg"               />
        <Reactant specieID="DhpgMglu"             />
        <Product  specieID="GabgDhpgMglu"            />

        <forwardRate>  15e-06  </forwardRate>
        <reverseRate>   7.2e-03  </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

   <!-- GabgDhpgMglu    <-> GaGTP + DhpgMglu    -->
    <Reaction name = "GabgDhpgMglu--GaGTP+DhpgMglu" id="GabgDhpgMglu--GaGTP+DhpgMglu">
        <Reactant specieID="GabgDhpgMglu"               />
        <Product specieID="GaGTP"             />
        <Product  specieID="DhpgMglu"            />

        <forwardRate>  0.5e-03 </forwardRate>
        <reverseRate>   0  </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

<!-- check thermodynamic equilibrium of next four reactions: NO GOOD.  Decrease affinity of PLC-GaGTP for Ca to 500 -->
    <!-- Plc + Ca    <->   PlcCa  6000 nM-->
<!--AB: this is REALLY fast - as fast as Cam binding to calcium.  Might want to slow down both calcium binding steps?
Yes, by 5x (no change affinity) Nov 30.  Keep affinity of Plc for Ca = 6 uM (low) -->
    <Reaction name = "Plc+Ca--PlcCa" id="Plc+Ca--PlcCa">
        <Reactant specieID="Ca"           />
        <Reactant specieID="Plc"              />
        <Product  specieID="PlcCa"               />

        <forwardRate> 0.020e-03   </forwardRate>
        <reverseRate> 120e-03        </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>
 
    <!-- Plc + GaGTP    <->   PlcGaGTP 1200 nM -->
<!--AB: Falkenburger 2010 uses 0.71e-3 for reverse rate --> 
<!--Kf is 10x lower for PLC - GaGTP than Jan31 reac -->
    <Reaction name = "Plc+GaGTP--PlcGaGTP" id="Plc+GaGTP--PlcGaGTP">
        <Reactant specieID="GaGTP"           />
        <Reactant specieID="Plc"              />
        <Product  specieID="PlcGaGTP"               />

        <forwardRate> 0.010e-03   </forwardRate>
        <reverseRate> 12e-03        </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

    <!-- PlcGaGTP + Ca    <->   PlcCaGaGTP  500 nM-->
    <Reaction name = "PlcGaGTP+Ca--PlcCaGaGTP" id="PlcGaGTP+Ca--PlcCaGaGTP">
        <Reactant specieID="Ca"           />
        <Reactant specieID="PlcGaGTP"              />
        <Product  specieID="PlcCaGaGTP"               />

        <forwardRate> 0.08e-03   </forwardRate>
        <reverseRate> 40e-03        </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

    <!-- PlcCa + GaGTP    <->   PlcCaGaGTP  100 nM-->
<!--decrease these rates Nov 30 (same affinity) by 3x -->
<!--Kf is 10x lower for PLC - GaGTP than Jan31 reac -->
    <Reaction name = "PlcCa+GaGTP--PlcCaGaGTP" id="PlcCa+GaGTP--PlcCaGaGTP">
        <Reactant specieID="GaGTP"           />
        <Reactant specieID="PlcCa"              />
        <Product  specieID="PlcCaGaGTP"               />

        <forwardRate> 0.10e-03   </forwardRate>
        <reverseRate> 10e-03        </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>
 
   <!-- PlcCa + Pip2    <-> PlcCaPip2    -->
<!--No affinities for Pip2 are found in literature.  ALso, backward rate is very low compared to kcat
This will initiall have small effect on Km, but might slow down IP3 production.
Incraese Kb by 5x to decrease Ip3 production-->
<!-- Decrease Kf by 10x to compensate for 10x inc in Pip2-->
<!-- decrease the next two set of rates 5x overall since too much Pip2 is being hydrolyzed at basal calcium Nov 30 -->
    <Reaction name = "PlcCa+Pip2--PlcCaPip2" id="PlcCa+Pip2--PlcCaPip2">
        <Reactant specieID="PlcCa"               />
        <Reactant specieID="Pip2"             />
        <Product  specieID="PlcCaPip2"            />

        <forwardRate> 0.6e-06   </forwardRate>
        <reverseRate>  10e-03   </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>
      

    <!-- PlcCaPip2      <-> PlcCaDag + Ip3 -->
    <Reaction name = "PlcCaPip2--PlcCaDag+Ip3" id="PlcCaPip2--PlcCaDag+Ip3">
        <Reactant specieID="PlcCaPip2"            />
        <Product  specieID="PlcCaDag"               />
        <Product  specieID="Ip3"            />

        <forwardRate> 25e-03     </forwardRate>
        <reverseRate> 0e-03    </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>
      
    <!-- PlcCaDag       <->  PlcCa + Dag -->
    <Reaction name = "PlcCaDag--PlcCa+Dag" id="PlcCaDag--PlcCa+Dag">
        <Reactant specieID="PlcCaDag"            />
        <Product  specieID="PlcCa"               />
        <Product  specieID="Dag"            />

        <forwardRate> 200e-03     </forwardRate>
        <reverseRate> 0e-03    </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>    

   <!-- PlcCaGaGTP + Pip2    <-> PlcCaGaGTPPip2    -->
<!-- Decrease Kf by 10x to compensate for 10x inc in Pip2-->
<!-- Decrease rates by 2x to maintain 10x enhancement by GaGTP Nov 30
Increse Kb by 5x to decrease Ip3 production-->
    <Reaction name = "PlcCaGaGTP+Pip2--PlcCaGaGTPPip2" id="PlcCaGaGTP+Pip2--PlcCaGaGTPPip2">
        <Reactant specieID="PlcCaGaGTP"               />
        <Reactant specieID="Pip2"             />
        <Product  specieID="PlcCaGaGTPPip2"            />

        <forwardRate>  15e-06   </forwardRate>
        <reverseRate>  75e-03   </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>
      
    <!-- PlcCaGaGTPPip2       <-> PlcCaGaGTPDag + Ip3 -->
    <Reaction name = "PlcCaGaGTPPip2--PlcCaGaGTPDag+Ip3" id="PlcCaGaGTPPip2--PlcCaGaGTPDag+Ip3">
        <Reactant specieID="PlcCaGaGTPPip2"            />
        <Product  specieID="PlcCaGaGTPDag"               />
        <Product  specieID="Ip3"            />

        <forwardRate> 250e-03     </forwardRate>
        <reverseRate> 0e-03    </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>
      
    <!-- PlcCaGaGTPDag       <->  PlcCaGaGTPTp + Dag -->
    <Reaction name = "PlcCaGaGTPDag--PlcCaGaGTPTp+Dag" id="PlcCaGaGTPDag--PlcCaGaGTPTp+Dag">
        <Reactant specieID="PlcCaGaGTPDag"            />
        <Product  specieID="PlcCaGaGTP"               />
        <Product  specieID="Dag"            />

        <forwardRate> 1000e-03     </forwardRate>
        <reverseRate> 0e-03    </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>    

<!--  What if PIP2 can only be regenerated from degraded IP3 by membrane molecule.
Thus, initialize PIkinase in the membrane only. 
No idea what these rates should be.  Try different values to obtain equilibirum at basal
These rates interact with PIkinase quantity. Affinity started at 1 uM
Discovered mistake!!! specified PIkinase as product, not reactant!-->
   <Reaction name = "Ip3degrad + PIkinase -- Ip3degPIkinase" id="PIkinase1">
        <Reactant specieID="Ip3degrad"            />   
        <Reactant  specieID="PIkinase"               />
        <Product  specieID="Ip3degPIk"            />

        <forwardRate> 2.0e-6    </forwardRate>
        <reverseRate> 1e-03    </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

<!-- Initial rate from PI5kinase from Falkenburger, increased to compensate for lower reactant quantity -->
   <Reaction name = "Ip3degPIkinase -- PIP2 + PIkinase" id="PIkinase2">
        <Reactant specieID="Ip3degPIk"            />
        <Product  specieID="PIkinase"               />
        <Product  specieID="Pip2"            />

        <forwardRate> 1e-3  </forwardRate>
        <reverseRate> 0e-03    </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>    

<!-- GAP activity - only with PLC bound neither to calcium nor PIP2 -->
    <!-- PlcGaGTP       <-> Plc + Gabg -->
	<!-- When PLC hydrolyzes GaGTP, the GaGDP immediately binds to Gbg to regenerate Gabg
	This saves two reactions: not only the rebinding, but also Gbg dissociating from the mGluR after GaGTP
	Given the speed of the rebinding and dissociation in previous models, this is a wise choice
	However, it prevents depletion of Gabg! -->
    <Reaction name = "PlcGaGTP--Plc+GaGDP" id="PlcGaGTP--Plc+GaGDP">
        <Reactant specieID="PlcGaGTP"            />
        <Product  specieID="Plc"               />
        <Product  specieID="GaGDP"            />

        <forwardRate>   30e-03   </forwardRate>
        <reverseRate>   0  </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

<!-- Gap activity of PlcCa -->
    <Reaction name = "PlcCaGaGTP--PlcCa+GaGDP" id="PlcCaGaGTP--Plc+GaGDP">
        <Reactant specieID="PlcCaGaGTP"            />
        <Product  specieID="PlcCa"               />
        <Product  specieID="GaGDP"            />

        <forwardRate>   30e-03   </forwardRate>
        <reverseRate>   0  </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

<!-- Hydrolysis of GaGTP - slower than GAP activity-->
    <Reaction name = "GaGTP--GaGDP" id="GaGTP--GaGDP">
        <Reactant specieID="GaGTP"            />
        <Product  specieID="GaGDP"            />

        <forwardRate>   1e-03   </forwardRate>
        <reverseRate>   0  </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

<!-- 1st order regeneration of Gabg 
avoids the need to generate Gbg, and have them react-->
    <Reaction name = "GaGDP--Gabg" id="GaGDP--Gabg">
        <Reactant specieID="GaGDP"            />
        <Product  specieID="Gabg"            />

        <forwardRate>   10e-03   </forwardRate>
        <reverseRate>   0  </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

    <!-- Ca + Dgl <-> CaDgl   Dgl is DAG lipase, which produces 2AG -->
<!-- no source for rates.  Make slower, and also 400 nM affinity -->
    <Reaction name = "Ca+Dlg--CaDgl" id="Ca+Dlg--CaDgl">
        <Reactant specieID="Ca"            />
        <Reactant specieID="Dgl"               />
        <Product  specieID="CaDgl"            />

        <forwardRate> 0.125e-03     </forwardRate>
        <reverseRate> 50e-03    </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>
 
    <!-- Dag + CaDgl <-> DagCaDgl -->
    <!--affinity = 1010 nM IS there are publication on this? 
So far only 1 found: Bisogno J Cell Biol 2003
lists affinity of 75 uM or 154 uM "within the range found in tissue" -->
    <Reaction name = "Dag+CaDlg--DagCaDgl" id="Dag+CaDlg--DagCaDgl">
        <Reactant specieID="Dag"            />
        <Reactant specieID="CaDgl"               />
        <Product  specieID="DagCaDgl"            />

        <forwardRate> 1.25e-06     </forwardRate>
        <reverseRate> 0.75e-03    </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

<!-- raise kb to 1.5e-3 to create 1 uM affinity
also make all rates even (4x) slower to saturate at lower Dag? -->
    <!-- DagCaDgl <-> CaDgl + 2ag -->
    <Reaction name = "DagCaDgl--CaDgl+2ag" id="DagCaDgl--CaDgl+2ag">
        <Reactant specieID="DagCaDgl"            />
        <Product  specieID="CaDgl"               />
        <Product  specieID="2ag"            />

        <forwardRate> 0.5e-03     </forwardRate>
        <reverseRate> 0e-03    </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

	<!-- ************* degradation of IP3 and 2AG, implementing the enzymes? -->
    <!--  Ip3    <-> Ip3degrad          Degraded IP3-->
    <Reaction name = "Ip3--Ip3degrad" id="Ip3--Ip3degrad">
         <Reactant specieID="Ip3"            />
        <Product  specieID="Ip3degrad"        />

        <forwardRate> 10e-03      </forwardRate>
        <reverseRate> 0.0e-03      </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

    <!--  2ag    <-> 2agDegrad       Degraded 2AG   -->
    <Reaction name = "2ag--2agDegrad" id="2ag--2agDegrad">
         <Reactant specieID="2ag"            />
        <Product  specieID="2agDegrad"        />

        <forwardRate> 5e-03      </forwardRate>
        <reverseRate> 0.0e-03      </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

	<!-- ************* degradation of  DAG by DAG kinase -->
     <!--  Dag   + DagK <-> DagKdag -> PA  step 1  (0.07 mM Km - What is pub for this?) -->
    <Reaction name = "DagKdag1" id="DagKdag1">
         <Reactant specieID="Dag"            />
         <Reactant specieID="DagK"            />
        <Product  specieID="DagKdag"        />

        <forwardRate> 0.7e-06      </forwardRate>
        <reverseRate> 0.04         </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

    <!--  Dag   + DagK <-> DagKdag -> PA   step 2 (Kcat is on the high side, could be half the rate)-->
    <Reaction name = "DagKdag1" id="DagKdag1">
         <Reactant specieID="DagKdag"            />
        <Product  specieID="PA"        />

        <forwardRate> 10e-03      </forwardRate>
        <reverseRate> 0.0e-03      </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>


<!-- THese are values from Hellgren Kotaleski PKC paper. 2.5 uM affinity -->
    <!-- Pkc + Ca    <->   PkcCa  -->
    <Reaction name = "Pkc+Ca--PkcCa" id="Pkc+Ca--PkcCa">
        <Reactant specieID="Ca"           />
        <Reactant specieID="Pkc"              />
        <Product  specieID="PkcCa"               />

        <forwardRate> 20e-06   </forwardRate>
        <reverseRate> 50e-03        </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>
 
<!-- THese are values from Hellgren Kotaleski PKC paper. 10 uM affinity
MUCH slower binding compared to CaDgl  -->
   <!-- PkcCa + Dag    <-> Pkct    -->
    <Reaction name = "PkcCa+Dag--Pkct" id="PkcCa+Dag--Pkct">
        <Reactant specieID="PkcCa"               />
        <Reactant specieID="Dag"             />
        <Product  specieID="Pkct"            />

        <forwardRate> 0.015e-06   </forwardRate>
        <reverseRate>  0.15e-03   </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>


</ReactionScheme>