Compartmental differences in cAMP signaling pathways in hippocam. CA1 pyr. cells (Luczak et al 2017)

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Accession:245529
Model of cAMP signaling pathways in hippocampal CA1 pyramidal neurons investigate mechanisms underlying the experimentally observed difference in cAMP and PKA FRET between proximal and distal dendrites. Simulations show that compartmental difference in PKA activity required enrichment of protein phosphatase in small compartments; neither reduced PKA subunits nor increased PKA substrates were sufficient.
Reference:
1 . Luczak V, Blackwell KT, Abel T, Girault JA, Gervasi N (2017) Dendritic diameter influences the rate and magnitude of hippocampal cAMP and PKA transients during ß-adrenergic receptor activation. Neurobiol Learn Mem 138:10-20 [PubMed]
Model Information (Click on a link to find other models with that property)
Model Type: Molecular Network;
Brain Region(s)/Organism: Hippocampus; Mouse;
Cell Type(s): Hippocampus CA1 pyramidal GLU cell;
Channel(s):
Gap Junctions:
Receptor(s): Adrenergic;
Gene(s):
Transmitter(s): Norephinephrine;
Simulation Environment:
Model Concept(s): G-protein coupled; Influence of Dendritic Geometry; Reaction-diffusion;
Implementer(s): Blackwell, Avrama [avrama at gmu.edu];
Search NeuronDB for information about:  Hippocampus CA1 pyramidal GLU cell; Adrenergic; Norephinephrine;
<ReactionScheme>
    <!-- You can specify the units of the diffusion constant. If they are not
	 specified they are assumed to be micron^2/second, (microns written "mu" here).
	 It should understand microns, mm, and m for distances and seconds and ms for times. -->

    <Specie name="Epac1" id="Epac1" kdiff="10" kdiffunit="mu2/s"/>
    <Specie name="Epac1cAMP" id="Epac1cAMP" kdiff="10" kdiffunit="mu2/s"/>

    <Specie name="L" id="L" kdiff="111.3" kdiffunit="mu2/s"/>
    <Specie name="LOut" id="LOut" kdiff="111.3" kdiffunit="mu2/s"/>

    <Specie name="cAMP" id="cAMP" kdiff="86.4" kdiffunit="mu2/s"/>
    <Specie name="ATP" id="ATP" kdiff="74.7" kdiffunit="mu2/s"/>
    <Specie name="AMP" id="AMP" kdiff="85.5" kdiffunit="mu2/s"/>

    <Specie name="R" id="R" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="Gs" id="Gs" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="GsR" id="GsR" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="LR" id="LR" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="LRGs" id="LRGs" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="PKAcLRGs" id="PKAcLRGs" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="pLRGs" id="pLRGs" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="GasGTP" id="GasGTP" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="GasGDP" id="GasGDP" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="Gbg" id="Gbg" kdiff="0" kdiffunit="mu2/s"/>

<!-- calcium stuff  -->
    <Specie name="Ca"          id="Ca"          kdiff="174.3" 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"/>

    <!-- Cam and PP2B-->     
    <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="PP2B"        id="PP2B"        kdiff="0"     kdiffunit="mu2/s"/>
    <Specie name="PP2BCam"     id="PP2BCam"     kdiff="0"     kdiffunit="mu2/s"/>
    <Specie name="PP2BCamCa2C" id="PP2BCamCa2C" kdiff="0"     kdiffunit="mu2/s"/>
    <Specie name="PP2BCamCa2N" id="PP2BCamCa2N" kdiff="0"     kdiffunit="mu2/s"/>
    <Specie name="PP2BCamCa4"  id="PP2BCamCa4"  kdiff="0"     kdiffunit="mu2/s"/>

<!-- AC, PKA -->
    <Specie name="AC1" id="AC1" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="AC1GasGTP" id="AC1GasGTP" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="AC1GasCamCa4" id="AC1GasCamCa4" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="AC1GasCamCa4ATP" id="AC1GasCamCa4ATP" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="AC1CamCa4" id="AC1CamCa4" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="AC1CamCa4ATP" id="AC1CamCa4ATP" kdiff="0" kdiffunit="mu2/s"/>

    <Specie name="AC5"         id="AC5"         kdiff="0"    kdiffunit="mu2/s"/>
    <Specie name="AC5Gas"      id="AC5Gas"      kdiff="0"    kdiffunit="mu2/s"/>
    <Specie name="AC5GasATP"   id="AC5GasATP"   kdiff="0"    kdiffunit="mu2/s"/>

<!-- PKA -->
    <Specie name="PKA"        id="PKA"         kdiff="0"     kdiffunit="mu2/s"/>
    <Specie name="PKAcAMP2"   id="PKAcAMP2"    kdiff="0"     kdiffunit="mu2/s"/>
    <Specie name="PKAcAMP4"   id="PKAcAMP4"    kdiff="0"     kdiffunit="mu2/s"/>
    <Specie name="PKAc"       id="PKAc"        kdiff="0.836" kdiffunit="mu2/s"/>
    <Specie name="PKAr"       id="PKAr"        kdiff="0"     kdiffunit="mu2/s"/>

<!-- PDE4 only -->
    <Specie name="PDE4" id="PDE4" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="PDE4cAMP" id="PDE4cAMP" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="PKAcPDE4" id="PKAcPDE4" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="pPDE4" id="pPDE4" kdiff="0" kdiffunit="mu2/s"/>
    <Specie name="pPDE4cAMP" id="pPDE4cAMP" kdiff="0" kdiffunit="mu2/s"/>
   
<!-- ###################### Reactions, parameters ##########################-->

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

        <forwardRate>0.028e-3</forwardRate>
        <reverseRate>19.6</reverseRate>
        <Q10>0.2</Q10>
    </Reaction>

<!--1A) Cam  + 2Ca <-> CamCa2C GQ RXN FILE, C or N can bind first-->
    <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>

<!--2A) CamCa2C  + 2Ca <-> CamCa4 GQ RXN FILE, C or N can bind first-->
    <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>

<!--1B) Cam  + 2Ca <-> CamCa2N GQ RXN FILE, C or N can bind first-->
    <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>

<!--2B) CamCa2N  + 2Ca <-> CamCa4 GQ RXN FILE, C or N can bind first-->
    <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>

<!-- L Buffer-    L <-> LOut -->
<!--
    <Reaction name = "L_buffer" id="L_Buffer">
	<Reactant specieID="L"/>
	<Product specieID="LOut"/>

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

<!-- 1) L + R <-> LR    -->
    <Reaction name = "LR_bind" id="LR_bind">
	<Reactant specieID="L"/>
	<Reactant specieID="R"/>
	<Product specieID="LR"/>

	<forwardRate>0.005555e-3</forwardRate>
	<reverseRate>5e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!-- 2) LR + Gs <-> LRGs    -->
    <Reaction name = "LRGs_bind" id="LRGs_bind">
	<Reactant specieID="LR"/>
	<Reactant specieID="Gs"/>
	<Product specieID="LRGs"/>

	<forwardRate>0.0006e-3</forwardRate>
	<reverseRate>0.001e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!-- 3) Gs + R <-> GsR    -->
    <Reaction name = "GsR_bind" id="GsR_bind">
	<Reactant specieID="Gs"/>
	<Reactant specieID="R"/>
	<Product specieID="GsR"/>

	<forwardRate>0.00004e-3</forwardRate>
	<reverseRate>0.0003e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!-- 4) GsR + L <-> LRGs    -->
    <Reaction name = "GsRL_bind" id="GsRL_bind">
	<Reactant specieID="GsR"/>
	<Reactant specieID="L"/>
	<Product specieID="LRGs"/>

	<forwardRate>0.0025e-3</forwardRate>
	<reverseRate>0.5e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!-- 5a) LRGs -> LRGbg + GasGTP -->
    <Reaction name = "GasGTP_bind" id="GasGTP_bind">
	<Reactant specieID="LRGs"/>
	<Product specieID="LR"/>
	<Product specieID="Gbg"/>
	<Product specieID="GasGTP"/>

	<forwardRate>2e-3</forwardRate>
	<reverseRate>0</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>
<!-- Above reactions are fine - thermodynamically balanced.-->

<!--*****************PKAc phosphorylation of LRGs *******************************-->
    <!--1a. PKAc + LRGs -> PKAcLRGs  Km=120 nM -->
    <Reaction name = "LRGs phosp1" id="phospLRGs1">
        <Reactant specieID="PKAc"                   />
        <Reactant specieID="LRGs"                  />
        <Product  specieID="PKAcLRGs"              />

        <forwardRate> 0.00125e-03    </forwardRate>
        <reverseRate> 0.16e-03    </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>
    <!--2a. PKAcLRGs -> PKAc + pLRGs -->
    <Reaction name = "LRGs phosp2" id="phospLRGs2">
        <Reactant specieID="PKAcLRGs"              />
        <Product  specieID="pLRGs"                 />
        <Product  specieID="PKAc"                   />

        <forwardRate> 0.04e-03    </forwardRate>
        <reverseRate> 0             </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

    <!--3. pLRGs -> LRGs -->
    <Reaction name = "dephosD1R" id="dphospD1R">
        <Reactant specieID="pLRGs"              />
        <Product  specieID="LRGs"               />

        <forwardRate>  0.003e-03    </forwardRate>
        <reverseRate>  0            </reverseRate>
        <Q10>          0.2          </Q10>
    </Reaction>

<!-- 6a) GasGTP -> GasGDP    -->
    <Reaction name = "GasGTP_disso" id="GasGTP_disso">
	<Reactant specieID="GasGTP"/>
	<Product specieID="GasGDP"/>

        <forwardRate>0.5e-3</forwardRate>
	<reverseRate>0</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!-- 7a) GasGDP + Gbg -> Gs    -->
    <Reaction name = "Gs_form" id="Gs_form">
	<Reactant specieID="GasGDP"/>
        <Reactant specieID="Gbg"/>
	<Product specieID="Gs"/>

        <forwardRate>10e-3</forwardRate>
	<reverseRate>0</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>


<!-- AC part: AC1 activation through CamCa4  -->

<!-- 1a) GasGTP + AC1 <-> AC1GasGTP   -->
    <Reaction name = "GasGTP_AC1_reac" id="GasGTP_AC1_reac">
	<Reactant specieID="GasGTP"/>
	<Reactant specieID="AC1"/>
	<Product specieID="AC1GasGTP"/>

	<forwardRate>0.0385e-3</forwardRate>
	<reverseRate>10e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

    <Reaction name = "AC1_GasGTP_hydrolysis" id="AC1_GasGTP_GAP">
	<Reactant specieID="AC1GasGTP"/>
	<Product specieID="AC1"/>
	<Product specieID="GasGDP"/>
        <forwardRate>1e-3</forwardRate>
	<reverseRate>0</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!-- 1b) AC1GasGTP + CamCa4 <-> AC1GasCamCa4    -->
    <Reaction name = "AC1GasGTP_CamCa4_Reac" id="AC1GasGTP_CamCa4_Reac">
	<Reactant specieID="AC1GasGTP"/>
	<Reactant specieID="CamCa4"/>
	<Product specieID="AC1GasCamCa4"/>

	<forwardRate>0.006e-3</forwardRate>
	<reverseRate>0.9e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>
    
<!-- all ATP binding slowed down 10x to avoid needing much smaller dt. -->
<!-- 1c) AC1GasCamCa4 + ATP <-> AC1GasCamCa4ATP    -->
    <Reaction name = "AC1GasCamCa4_ATP_Reac" id="AC1GasCamCa4_ATP_Reac">
	<Reactant specieID="AC1GasCamCa4"/>
	<Reactant specieID="ATP"/>
	<Product specieID="AC1GasCamCa4ATP"/>

	<forwardRate>0.001e-3</forwardRate>
	<reverseRate>114e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!-- 1d) AC1GasCamATP -> AC1GasCam + cAMP    -->
    <Reaction name = "AC1GasCamCa4ATP_diss" id="AC1GasCamCa4ATP_diss">
	<Reactant specieID="AC1GasCamCa4ATP"/>
	<Product specieID="cAMP"/>
	<Product specieID="AC1GasCamCa4"/>

	<forwardRate>28.46e-3</forwardRate>
	<reverseRate>0</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!-- 5a) AC1 + CamCa4 <-> AC1Cam    -->
    <Reaction name = "AC1CamCa4_Reac" id="AC1CamCa4_Reac">
	<Reactant specieID="AC1"/>
	<Reactant specieID="CamCa4"/>
	<Product specieID="AC1CamCa4"/>

	<forwardRate>0.006e-3</forwardRate>
	<reverseRate>0.9e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!-- 5b) AC1Cam + ATP <-> AC1CamATP    -->
    <Reaction name = "AC1CamCa4ATP_bind" id="AC1CamCa4ATP_bind">
	<Reactant specieID="AC1CamCa4"/>
	<Reactant specieID="ATP"/>
	<Product specieID="AC1CamCa4ATP"/>

	<forwardRate>0.001e-3</forwardRate>
	<reverseRate>114e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!-- 5c) AC1CamATP -> AC1Cam +cAMP    -->
    <Reaction name = "AC1CamCa4ATP_disso" id="AC1CamCa4ATP_disso">
	<Reactant specieID="AC1CamCa4ATP"/>
	<Product specieID="cAMP"/>
	<Product specieID="AC1CamCa4"/>

	<forwardRate>2.846e-3</forwardRate>
	<reverseRate>0</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!--**************   V. AC5  ************** -->
    <!--1a. GasGTP + AC5 <-> AC5Gas(GTP) -->
    <Reaction name = "GasGTP+AC5--AC5Gas reac" id="GasGTP+AC5--AC5Gas_id">
        <Reactant specieID="GasGTP"                  />
        <Reactant specieID="AC5"                     />
        <Product  specieID="AC5Gas"                />
        <forwardRate> 0.00037e-03   </forwardRate>
        <reverseRate> 0.1e-03        </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>
    <!--2a. AC5Gas(GTP) + ATP    <-> AC5Gas(GTP)ATP     -->
    <Reaction name = "AC5Gas+ATP--AC5GasATP reac" id="AC5Gas+ATP--AC5GasATP_id">
        <Reactant specieID="AC5Gas"                />
        <Reactant specieID="ATP"                    />
        <Product  specieID="AC5GasATP"             />

        <forwardRate> 0.1276e-6    </forwardRate>
        <reverseRate> 0.2612e-03    </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>
    <!--3a. AC5Gas(GTP)ATP       <-> AC5Gas(GTP) + cAMP   -->
    <Reaction name = "AC5GasATP--AC5Gas+cAMP reac" id="AC5GasATP--AC5Gas+cAMP_id">
        <Reactant specieID="AC5GasATP"             />
        <Product  specieID="AC5Gas"                />
        <Product  specieID="cAMP"                   />

        <forwardRate> 28.46e-03     </forwardRate>
        <reverseRate> 0.2592e-6    </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>
    
    <!-- PKA part. 3x faster than previous based on some FRET imaging -->
    <!--1) PKA + 2cAMP <-> PKAcAMP2 -->
    <Reaction name = "PKA_bind" id="PKA_bind">
	<Reactant specieID="PKA"/>
        <Reactant specieID="cAMP" n="2"/>
	<Product specieID="PKAcAMP2"/>


        <forwardRate>0.261e-6</forwardRate>
	<reverseRate>0.06e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

    <!--2) PKAcAMP2 + 2cAMP <-> PKAcAMP4 -->
    <Reaction name = "PKAcAMP2_bind" id="PKAcAMP2_bind">
	<Reactant specieID="PKAcAMP2"/>
        <Reactant specieID="cAMP" n="2"/>
	<Product specieID="PKAcAMP4"/>

    <forwardRate>0.346e-6</forwardRate>
	<reverseRate>0.6e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!--11c) PKAcAMP4 <-> PKAr + 2PKAc -->
    <Reaction name = "PKAcAMP4diss2" id="PKAcAMP4diss2">
	<Reactant specieID="PKAcAMP4"/>
	<Product specieID="PKAr"/>
	<Product specieID="PKAc" n="2"/>

	<forwardRate>0.048e-3</forwardRate>
	<reverseRate>0.0051e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

<!--Epac-S^H14 EC50=4.4 uM (Polito et al. Fronteirs 2013)   -->
    <!--1) Epac + cAMP <-> Epac_cAMP -->
    <Reaction name = "PKA_bind" id="PKA_bind">
	<Reactant specieID="Epac1"/>
        <Reactant specieID="cAMP"/>
	<Product specieID="Epac1cAMP"/>

        <forwardRate>0.033e-6</forwardRate>
	<reverseRate>0.1452e-3</reverseRate>
	<Q10>0.2</Q10>
    </Reaction>

 <!-- ************** PDE Part ***************** -->

<!--6) AMP -> ATP  -->
       <Reaction name = "ATP_regen" id="ATP_regen">
	<Reactant specieID="AMP"/>
	<Product specieID="ATP"/>

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

<!-- Below PDE4B/D reactions from Rodrigo:PKAc compete with I1 and PDE4B/D -->
<!-- Current affinity with PKAc to PDE4B/D too high so nothing left binding for I1-->
<!-- Andrew 10/29/10: Condensed all PDE4B/D to PDE4 -->
    <!-- 07)  cAMP + PDE4  <-> PDE4cAMP -->
    <Reaction name = "PDE4 enzyme1" id="PDE4bind">
        <Reactant specieID="PDE4"           />
        <Reactant specieID="cAMP"            />
        <Product  specieID="PDE4cAMP"       />
        <forwardRate> 0.02166e-03  </forwardRate>
        <reverseRate> 68.950e-03    </reverseRate>
        <Q10>         0.2          </Q10>
    </Reaction>

    <!-- 08)  PDE4cAMP -> AMP + PDE4 -->
    <Reaction name = "PDE4 actvcomp" id="PDE4cat">
        <Reactant specieID="PDE4cAMP"       />
        <Product  specieID="PDE4"           />
        <Product  specieID="AMP"             />
        <forwardRate> 17.233e-03    </forwardRate>
        <reverseRate> 0            </reverseRate>
        <Q10>         0.2          </Q10>
    </Reaction>

    <!-- 09)  PKAc + PDE4 -> PKAcPDE4 Kd=320 nM -->
    <Reaction name = "PDE4 phosp1" id="phospPDE41">
        <Reactant specieID="PKAc"            />
        <Reactant specieID="PDE4"           />
        <Product  specieID="PKAcPDE4"       />
        <forwardRate> 0.214e-06  </forwardRate>
        <reverseRate> 0.056e-03      </reverseRate>
        <Q10>         0.2          </Q10>
    </Reaction>

    <!-- 10)  PKAcPDE4 -> PKAc + pPDE4 -->
    <Reaction name = "PDE4 phosp2" id="phospPDE42">
        <Reactant specieID="PKAcPDE4"       />
        <Product  specieID="pPDE4"          />
        <Product  specieID="PKAc"            />
        <forwardRate> 0.0125e-03     </forwardRate>
        <reverseRate> 0            </reverseRate>
        <Q10>         0.2          </Q10>
    </Reaction>

    <!-- 11)  pPDE4 -> PDE4 -->
    <Reaction name = "PDE4 d_phosp" id="dphospPDE4">
        <Reactant specieID="pPDE4"          />
        <Product  specieID="PDE4"           />
        <forwardRate> 0.00625e-03     </forwardRate>
        <reverseRate> 0            </reverseRate>
        <Q10>         0.2          </Q10>
    </Reaction>

    <!-- 12)  cAMP + pPDE4  <-> pPDE4cAMP, 4x rate as unphos PDE4 -->
    <Reaction name = "pPDE4 enzyme1" id="pPDE4bind">
        <Reactant specieID="pPDE4"           />
        <Reactant specieID="cAMP"             />
        <Product  specieID="pPDE4cAMP"       />
        <forwardRate> 0.0866e-03  </forwardRate>
        <reverseRate> 275.8e-03    </reverseRate>
        <Q10>         0.2          </Q10>
    </Reaction>

    <!-- 13)  pPDE4cAMP -> AMP + pPDE4 -->
    <Reaction name = "pPDE4 actvcomp" id="pPDE4cat">
        <Reactant specieID="pPDE4cAMP"       />
        <Product  specieID="pPDE4"           />
        <Product  specieID="AMP"              />
        <forwardRate> 68.92e-03    </forwardRate>
        <reverseRate> 0            </reverseRate>
        <Q10>         0.2          </Q10>
    </Reaction>

<!-- ******************* PP2B part ******************** -->
    <!--4x) Cam    +   PP2B     <->  PP2BCam     (in xpp: k33a=1 k_33a=3)  -->
    <Reaction name = "Cam+PP2B--PP2BCam reac" id="Cam+PP2B--PP2BCam_id">
        <Reactant specieID="Cam"                    />
        <Reactant specieID="PP2B"                   />
        <Product  specieID="PP2BCam"                />

        <forwardRate> 0.0046e-3       </forwardRate>
        <reverseRate> 0.0012e-3      </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

    <!--4C) CamCa2C    +   PP2B     <->  PP2BCamCa2C (in xpp: k33c=1 k_33c=0.3) -->
    <Reaction name = "CamCa2C+PP2B--PP2BCamCa2C reac" id="CamCa2C+PP2B--PP2BCamCa2C_id">
        <Reactant specieID="CamCa2C"                 />
        <Reactant specieID="PP2B"                   />
        <Product  specieID="PP2BCamCa2C"             />

        <forwardRate> 0.046e-3       </forwardRate>
        <reverseRate> 0.0012e-3      </reverseRate>
        <Q10>         0.2            </Q10>
    </Reaction>

    <!--4N) CamCa2N    +   PP2B     <->  PP2BCamCa2N (in xpp: k33c=1 k_33c=0.3) -->
    <Reaction name = "CamCa2N+PP2B--PP2BCamCa2N reac" id="CamCa2N+PP2B--PP2BCamCa2N_id">
        <Reactant specieID="CamCa2N"                 />
        <Reactant specieID="PP2B"                   />
        <Product  specieID="PP2BCamCa2N"             />

        <forwardRate> 0.046e-3       </forwardRate>
        <reverseRate> 0.0012e-3      </reverseRate>
        <Q10>         0.2            </Q10>
    </Reaction>

    <!--5xC) PP2BCam    +   Ca2      <->  PP2BCamCa2C -->
    <Reaction name = "PP2BCam+Ca2--PP2BCamCa2C reac" id="PP2BCam+Ca2--PP2BCamCa2C_id">
        <Reactant specieID="PP2BCam"                />
        <Reactant specieID="Ca"        n="2"        />
        <Product  specieID="PP2BCamCa2C"             />

        <forwardRate> 6.0e-06       </forwardRate>
        <reverseRate> 0.91e-03      </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

    <!--5xN) PP2BCam    +   Ca2      <->  PP2BCamCa2N -->
    <Reaction name = "PP2BCam+Ca2--PP2BCamCa2N reac" id="PP2BCam+Ca2--PP2BCamCa2N_id">
        <Reactant specieID="PP2BCam"                />
        <Reactant specieID="Ca"        n="2"        />
        <Product  specieID="PP2BCamCa2N"             />

        <forwardRate> 0.1e-03       </forwardRate>
        <reverseRate> 100e-03      </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

    <!--7x) CamCa4    +  PP2B     <->  PP2BCamCa4 -->
    <Reaction name = "CamCa4+PP2B--PP2BCamCa4 reac" id="CamCa4+PP2B--PP2BCamCa4_id">
        <Reactant specieID="CamCa4"                 />
        <Reactant specieID="PP2B"                   />
        <Product  specieID="PP2BCamCa4"             />

        <forwardRate> 0.046e-3       </forwardRate>
        <reverseRate> 0.0012e-3      </reverseRate>
        <Q10>         0.2            </Q10>
    </Reaction>

   <!--4C) C site binding -->
    <Reaction name = "PP2BCamCa2C+Ca2--PP2BCamCa4 reac" id="PP2BCamCa2+Ca2--PP2BCamCa4_id">
        <Reactant specieID="PP2BCamCa2C"             />
        <Reactant specieID="Ca"        n="2"        />
        <Product  specieID="PP2BCamCa4"             />

        <forwardRate> 0.1e-03       </forwardRate>
        <reverseRate> 1000e-03      </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

    <!--4N) N site binding -->
    <Reaction name = "PP2BCamCa2N+Ca2--PP2BCamCa4 reac" id="PP2BCamCa2N+Ca2--PP2BCamCa4_id">
        <Reactant specieID="PP2BCamCa2N"             />
        <Reactant specieID="Ca"        n="2"        />
        <Product  specieID="PP2BCamCa4"             />

        <forwardRate> 6.0e-06       </forwardRate>
        <reverseRate> 9.1e-03      </reverseRate>
        <Q10>         0.2           </Q10>
    </Reaction>

</ReactionScheme>


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