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BIOMD0000000635 - Nair2015 - Interaction between neuromodulators via GPCRs - Effect on cAMP/PKA signaling (D1 Neuron)

 

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Reference Publication
Publication ID: 26468202
Nair AG, Gutierrez-Arenas O, Eriksson O, Vincent P, Hellgren Kotaleski J.
Sensing Positive versus Negative Reward Signals through Adenylyl Cyclase-Coupled GPCRs in Direct and Indirect Pathway Striatal Medium Spiny Neurons.
J. Neurosci. 2015 Oct; 35(41): 14017-14030
Science for Life Laboratory, School of Computer Science and Communication, KTH Royal Institute of Technology, 11428 Stockholm, Sweden, Manipal University, 576104 Manipal, India.  [more]
Model
Original Model: BIOMD0000000635.origin
Submitter: Anu G Nair
Submission ID: MODEL1502200000
Submission Date: 20 Feb 2015 11:16:09 UTC
Last Modification Date: 02 May 2017 15:48:35 UTC
Creation Date: 02 May 2017 13:29:37 UTC
Encoders:  Ryan Gutenkunst
   Alyssa Fortier
   Niloufar Mollasalehi
   Anoop Hunjan
   janet Courtright
   Kevin Gee
set #1
bqbiol:hasProperty Gene Ontology dopamine uptake
Gene Ontology dopamine receptor signaling pathway
Gene Ontology G-protein coupled receptor activity
Gene Ontology adenylate cyclase activity
Mathematical Modelling Ontology MAMO_0000046
bqbiol:hasTaxon Taxonomy Mus musculus
Notes
Nair2015 - Interaction between neuromodulators via GPCRs - Effect on cAMP/PKA signaling (D1 Neuron)

This model is described in the article:

Nair AG, Gutierrez-Arenas O, Eriksson O, Vincent P, Hellgren Kotaleski J.
J. Neurosci. 2015 Oct; 35(41): 14017-14030

Abstract:

Transient changes in striatal dopamine (DA) concentration are considered to encode a reward prediction error (RPE) in reinforcement learning tasks. Often, a phasic DA change occurs concomitantly with a dip in striatal acetylcholine (ACh), whereas other neuromodulators, such as adenosine (Adn), change slowly. There are abundant adenylyl cyclase (AC) coupled GPCRs for these neuromodulators in striatal medium spiny neurons (MSNs), which play important roles in plasticity. However, little is known about the interaction between these neuromodulators via GPCRs. The interaction between these transient neuromodulator changes and the effect on cAMP/PKA signaling via Golf- and Gi/o-coupled GPCR are studied here using quantitative kinetic modeling. The simulations suggest that, under basal conditions, cAMP/PKA signaling could be significantly inhibited in D1R+ MSNs via ACh/M4R/Gi/o and an ACh dip is required to gate a subset of D1R/Golf-dependent PKA activation. Furthermore, the interaction between ACh dip and DA peak, via D1R and M4R, is synergistic. In a similar fashion, PKA signaling in D2+ MSNs is under basal inhibition via D2R/Gi/o and a DA dip leads to a PKA increase by disinhibiting A2aR/Golf, but D2+ MSNs could also respond to the DA peak via other intracellular pathways. This study highlights the similarity between the two types of MSNs in terms of high basal AC inhibition by Gi/o and the importance of interactions between Gi/o and Golf signaling, but at the same time predicts differences between them with regard to the sign of RPE responsible for PKA activation.Dopamine transients are considered to carry reward-related signal in reinforcement learning. An increase in dopamine concentration is associated with an unexpected reward or salient stimuli, whereas a decrease is produced by omission of an expected reward. Often dopamine transients are accompanied by other neuromodulatory signals, such as acetylcholine and adenosine. We highlight the importance of interaction between acetylcholine, dopamine, and adenosine signals via adenylyl-cyclase coupled GPCRs in shaping the dopamine-dependent cAMP/PKA signaling in striatal neurons. Specifically, a dopamine peak and an acetylcholine dip must interact, via D1 and M4 receptor, and a dopamine dip must interact with adenosine tone, via D2 and A2a receptor, in direct and indirect pathway neurons, respectively, to have any significant downstream PKA activation.

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 CC0 Public Domain Dedication for more information.

Model
Publication ID: 26468202 Submission Date: 20 Feb 2015 11:16:09 UTC Last Modification Date: 02 May 2017 15:48:35 UTC Creation Date: 02 May 2017 13:29:37 UTC
Mathematical expressions
Reactions
revreaction_1 revreaction_2 revreaction_3 revreaction_4
revreaction_5 revreaction_6 revreaction_7 revreaction_8
revreaction_9 revreaction_10 revreaction_11 revreaction_12
revreaction_13 revreaction_14 revreaction_15 revreaction_16
revreaction_17 revreaction_18 revreaction_19 revreaction_20
revreaction_21 revreaction_22 revreaction_23 revreaction_24
revreaction_25 revreaction_26 revreaction_27 revreaction_28
revreaction_29 revreaction_30 revreaction_31 revreaction_32
revreaction_33 revreaction_34 revreaction_35 revreaction_36
revreaction_37 revreaction_38 revreaction_39 revreaction_40
revreaction_41 revreaction_42 revreaction_43 revreaction_44
revreaction_45 revreaction_46 revreaction_47 revreaction_48
revreaction_49 revreaction_50 revreaction_51 revreaction_52
revreaction_53 revreaction_54 revreaction_55 revreaction_56
revreaction_57 revreaction_58 revreaction_59 revreaction_60
revreaction_61 irrevreaction_1 irrevreaction_2 irrevreaction_3
irrevreaction_4 irrevreaction_5 irrevreaction_6 irrevreaction_7
irrevreaction_8 irrevreaction_9 irrevreaction_10 irrevreaction_11
irrevreaction_12 irrevreaction_13 irrevreaction_14 irrevreaction_15
irrevreaction_16 irrevreaction_17 irrevreaction_18 irrevreaction_19
irrevreaction_20 irrevreaction_21 irrevreaction_22 irrevreaction_23
irrevreaction_24 irrevreaction_25 irrevreaction_26 irrevreaction_27
irrevreaction_28 irrevreaction_29 irrevreaction_30 irrevreaction_31
irrevreaction_32 irrevreaction_33 irrevreaction_34 irrevreaction_35
irrevreaction_36 irrevreaction_37 irrevreaction_38 irrevreaction_39
irrevreaction_40 irrevreaction_41 irrevreaction_42 irrevreaction_43
irrevreaction_44 irrevreaction_45 irrevreaction_46 irrevreaction_47
irrevreaction_48 irrevreaction_49 irrevreaction_50 irrevreaction_51
irrevreaction_52      
Rules
Assignment Rule (variable: totalActivePKA) Assignment Rule (variable: DApeak) Assignment Rule (variable: DApeak_minimum) Assignment Rule (variable: DA)
Assignment Rule (variable: AChdip) Assignment Rule (variable: AChdip_maximum) Assignment Rule (variable: ACh)  
Physical entities
Compartments Species
Spine GaiGTP GaolfGDP Gbgolf
GaolfGTP D1RDAGolf Golf
D1RGolf D1RDA D1R
cAMP Ca AC5
AC5GaolfGTP CaM CaMCa2
CaMCa4 PDE4 PKA
PKAcAMP2 PKAcAMP4 PKAreg
PKAc PP2B PP2Bc
PP2BCaM PP2BCaMCa2 DARPP32
PKAc*D32 D32p34 B72PP2A
PKAc*B56PP2A B56PP2Ap CDK5
PP1 CDK5*D32 D32p75
PKAcD32p75 B72PPA2Ca B56PP2Ap*D32p75
B72PP2A*D32p75 B72PP2ACa*D32p75 PP1D32p34
PP2Bc*D32p34 B72PP2A*D32p34 DA
AMP AC5Ca AC5CaGaolfGTP
AC5GaiGTP AC5CaGaiGTP B56PP2A
B56PP2A*D32p75 B72PP2ACa*D32p34 PDE4*cAMP
AC5GaolfGTPGaiGTP AC5CaGaolfGTPGaiGTP M4R
M4RACh M4RGi Gi
M4RAChGi Gbgi GaiGDP
ACh PDE10c PDE10
PDE10*cAMP PDE10c*cAMP ATP
AC5GaolfGTPGaiGTP*ATP AC5GaiGTP*ATP AC5GaolfGTP*ATP
AC5*ATP AC5CaGaolfGTP*ATP AC5CaGaiGTP*ATP
AC5CaGaolfGTPGaiGTP*ATP AC5Ca*ATP PP1*AKAR3p
PKAc*AKAR3 totalActivePKA  
Global parameters
krM4R*Gi kfM4R*Gi krPP2B*CaMCa2 kfPP2B*CaMCa2
krPP2BCaMCa2*2Ca kfPP2BCaMCa2*2Ca krPP2BCaM*2Ca kfPP2BCaM*2Ca
kfPP1*D32p34 krPP1*D32p34 kfPP2B*CaMCa4 krPP2B*CaMCa4
kfB72PP2A*Ca krB72PP2A*Ca kfPP2B*CaM krPP2B*CaM
kcatPKAc*D32 kGaolfGTPase kfPP2Bc*D32p34 krPP2Bc*D32p34
kfB56PP2A*D32p75 krB56PP2A*D32p75 kfB56PP2Ap*D32p75 krB56PP2Ap*D32p75
kcatB56PP2Ap*D32p75 kcatB56PP2A*D32p75 kcatB72PP2ACa*D32p75 kcatB72PP2A*D32p75
kfB72PP2A*D32p75 krB72PP2A*D32p75 kfB72PP2ACa*D32p75 krB72PP2ACa*D32p75
kcatPP2Bc*D32p34 kcatCDK5*D32 kactGi kGiGTPase
kGiback kfM4RACh*Gi krM4RACh*Gi kfPKA*2cAMP
krPKA*2cAMP krPKAc*PKAr kfPKAc*PKAr kfPKA2cAMP*2cAMP
krPKA2cAMP*2cAMP kfCDK5*D32 krCDK5*D32 kactGolf
kcatPDE4*cAMP kfPKAc*D32 krPKAc*D32 kfPDE4*cAMP
krPDE4*cAMP krPDE10*cAMP kcatPDE10c*cAMP kfPDE10*cAMP
kfcAMP*PDE10 krcAMP*PDE10 kcatcAMP*PDE10 kcatAC5GaolfGTP*ATP
kicatAC5GaolfGTP*ATP kcatAC5*ATP kicatAC5*ATP kcatAC5GaiGTP*ATP
kicatAC5GaiGTP*ATP kcatAC5CaGaiGTP*ATP kicatAC5CaGaiGTP*ATP kcatAC5Ca*ATP
kicatAC5Ca*ATP kcatAC5CaGaolfGTP*ATP kicatAC5CaGaolfGTP*ATP kfM4R*ACh
kfM4RGi*ACh krM4RGi*ACh krM4R*ACh kcatAC5GaolfGTPGaiGTP*ATP
kicatAC5GaolfGTPGaiGTP*ATP kicatAC5CaGaolfGTPGaiGTP*ATP kcatAC5CaGaolfGTPGaiGTP*ATP kfAC5*ATP
kfAC5CaGaolfGTP*ATP kfAC5CaGaiGTP*ATP kfAC5CaGaolfGTPGaiGTP*ATP kfCaM*2Ca
kGolfback krCaM*2Ca kdpB56PP2Ap krCaMCa2*2Ca
krPKAc*D32p75 kfPKAc*B56PP2A krPKAc*B56PP2A kfCaMCa2*2Ca
kcatPKAc*B56PP2A kfPKAc*D32p75 kfAC5GaolfGTP*ATP kfAC5GaiGTP*ATP
kfAC5GaolfGTPGaiGTP*ATP kfAC5Ca*ATP kfD1R*Golf krD1R*Golf
kfD1RDA*Golf krD1RDA*Golf kfB72PP2A*D32p34 krB72PP2A*D32p34
krAC5X*ATP kcatB72PP2A*D32p34 kfAC5XGaolfGTP kfAC5Ca
kfAC5XGaiGTP kfAC5XNCGaiGTP kfAC5XNCGaolfGTP krAC5XGaolfGTP
krAC5Ca krAC5XGaiGTP krAC5XNCGaiGTP krAC5XNCGaolfGTP
krgso krgsi kcatPP1*AKAR3p kfPP1*AKAR3p
krPP1*AKAR3p kcatPKAc*AKAR3 kfPKAc*AKAR3 krPKAc*AKAR3
kfPDE10c*cAMP krPDE10c*cAMP kfD1R*DA kfD1RGolf*DA
krD1R*DA krD1RGolf*DA DApeak_present DApeak
DApeak_steepness DApeak_startTime DApeak_duration DAbasal
DApeak_minimum DApeak_maximum AChdip_present AChdip
AChdip_steepness AChdip_startTime AChdip_duration AChbasal
AChdip_minimum AChdip_maximum Initial for AChbasal Initial for AChdip_duration
Initial for AChdip_maximum Initial for AChdip_minimum Initial for AChdip_present Initial for AChdip_startTime
Initial for AChdip_steepness Initial for DAbasal Initial for DApeak_duration Initial for DApeak_maximum
Initial for DApeak_minimum Initial for DApeak_present Initial for DApeak_startTime Initial for DApeak_steepness
Reactions (113)
 
 revreaction_1 [D1RGolf] + [DA] ↔ [D1RDAGolf];  
 
 revreaction_2 [D1RDA] + [Golf] ↔ [D1RDAGolf];  
 
 revreaction_3 [D1R] + [Golf] ↔ [D1RGolf];  
 
 revreaction_4 [D1R] + [DA] ↔ [D1RDA];  
 
 revreaction_5 [M4R] + [Gi] ↔ [M4RGi];  
 
 revreaction_6 [M4RACh] + [Gi] ↔ [M4RAChGi];  
 
 revreaction_7 [ACh] + [M4RGi] ↔ [M4RAChGi];  
 
 revreaction_8 [ACh] + [M4R] ↔ [M4RACh];  
 
 revreaction_9 [AC5] + [GaolfGTP] ↔ [AC5GaolfGTP];  
 
 revreaction_10 [AC5] + [Ca] ↔ [AC5Ca];  
 
 revreaction_11 [AC5Ca] + [GaolfGTP] ↔ [AC5CaGaolfGTP];  
 
 revreaction_12 [GaiGTP] + [AC5Ca] ↔ [AC5CaGaiGTP];  
 
 revreaction_13 [GaiGTP] + [AC5] ↔ [AC5GaiGTP];  
 
 revreaction_14 [GaiGTP] + [AC5GaolfGTP] ↔ [AC5GaolfGTPGaiGTP];  
 
 revreaction_15 [GaiGTP] + [AC5CaGaolfGTP] ↔ [AC5CaGaolfGTPGaiGTP];  
 
 revreaction_16 [AC5GaiGTP] + [GaolfGTP] ↔ [AC5GaolfGTPGaiGTP];  
 
 revreaction_17 [AC5CaGaiGTP] + [GaolfGTP] ↔ [AC5CaGaolfGTPGaiGTP];  
 
 revreaction_18 [AC5GaolfGTPGaiGTP] + [ATP] ↔ [AC5GaolfGTPGaiGTP*ATP];  
 
 revreaction_19 [ATP] + [AC5GaiGTP] ↔ [AC5GaiGTP*ATP];  
 
 revreaction_20 [AC5GaolfGTP] + [ATP] ↔ [AC5GaolfGTP*ATP];  
 
 revreaction_21 [AC5] + [ATP] ↔ [AC5*ATP];  
 
 revreaction_22 [AC5Ca] + [ATP] ↔ [AC5Ca*ATP];  
 
 revreaction_23 [AC5CaGaolfGTP] + [ATP] ↔ [AC5CaGaolfGTP*ATP];  
 
 revreaction_24 [AC5CaGaiGTP] + [ATP] ↔ [AC5CaGaiGTP*ATP];  
 
 revreaction_25 [AC5CaGaolfGTPGaiGTP] + [ATP] ↔ [AC5CaGaolfGTPGaiGTP*ATP];  
 
 revreaction_26 [GaolfGTP] + [AC5GaiGTP*ATP] ↔ [AC5GaolfGTPGaiGTP*ATP];  
 
 revreaction_27 [GaolfGTP] + [AC5CaGaiGTP*ATP] ↔ [AC5CaGaolfGTPGaiGTP*ATP];  
 
 revreaction_28 [GaolfGTP] + [AC5*ATP] ↔ [AC5GaolfGTP*ATP];  
 
 revreaction_29 [GaolfGTP] + [AC5Ca*ATP] ↔ [AC5CaGaolfGTP*ATP];  
 
 revreaction_30 [Ca] + [AC5*ATP] ↔ [AC5Ca*ATP];  
 
 revreaction_31 [AC5*ATP] + [GaiGTP] ↔ [AC5GaiGTP*ATP];  
 
 revreaction_32 [GaiGTP] + [AC5GaolfGTP*ATP] ↔ [AC5GaolfGTPGaiGTP*ATP];  
 
 revreaction_33 [AC5Ca*ATP] + [GaiGTP] ↔ [AC5CaGaiGTP*ATP];  
 
 revreaction_34 [GaiGTP] + [AC5CaGaolfGTP*ATP] ↔ [AC5CaGaolfGTPGaiGTP*ATP];  
 
 revreaction_35 [cAMP] + [PKA] ↔ [PKAcAMP2];  
 
 revreaction_36 [cAMP] + [PKAcAMP2] ↔ [PKAcAMP4];  
 
 revreaction_37 [PKAcAMP4] ↔ [PKAc] + [PKAreg];  
 
 revreaction_38 [cAMP] + [PDE4] ↔ [PDE4*cAMP];  
 
 revreaction_39 [PDE10] + 2.0 × [cAMP] ↔ [PDE10c];  
 
 revreaction_40 [cAMP] + [PDE10] ↔ [PDE10*cAMP];  
 
 revreaction_41 [cAMP] + [PDE10c] ↔ [PDE10c*cAMP];  
 
 revreaction_42 [CaM] + [Ca] ↔ [CaMCa2];  
 
 revreaction_43 [Ca] + [CaMCa2] ↔ [CaMCa4];  
 
 revreaction_44 [PP2B] + [CaM] ↔ [PP2BCaM];  
 
 revreaction_45 [PP2B] + [CaMCa4] ↔ [PP2Bc];  
 
 revreaction_46 [PKAc] + [DARPP32] ↔ [PKAc*D32];  
 
 revreaction_47 [PKAc] + [B56PP2A] ↔ [PKAc*B56PP2A];  
 
 revreaction_48 [D32p34] + [PP1] ↔ [PP1D32p34];  
 
 revreaction_49 [CDK5] + [DARPP32] ↔ [CDK5*D32];  
 
 revreaction_50 [D32p75] + [PKAc] ↔ [PKAcD32p75];  
 
 revreaction_51 [B72PP2A] + [Ca] ↔ [B72PPA2Ca];  
 
 revreaction_52 [B56PP2Ap] + [D32p75] ↔ [B56PP2Ap*D32p75];  
 
 revreaction_53 [B72PP2A] + [D32p75] ↔ [B72PP2A*D32p75];  
 
 revreaction_54 [D32p75] + [B72PPA2Ca] ↔ [B72PP2ACa*D32p75];  
 
 revreaction_55 [D32p34] + [PP2Bc] ↔ [PP2Bc*D32p34];  
 
 revreaction_56 [PP2BCaM] + [Ca] ↔ [PP2BCaMCa2];  
 
 revreaction_57 [PP2BCaMCa2] + [Ca] ↔ [PP2Bc];  
 
 revreaction_58 [PP2B] + [CaMCa2] ↔ [PP2BCaMCa2];  
 
 revreaction_59 [D32p75] + [B56PP2A] ↔ [B56PP2A*D32p75];  
 
 revreaction_60 [D32p34] + [B72PPA2Ca] ↔ [B72PP2ACa*D32p34];  
 
 revreaction_61 [D32p34] + [B72PP2A] ↔ [B72PP2A*D32p34];  
 
 irrevreaction_1 [GaolfGTP] → [GaolfGDP];  
 
 irrevreaction_2 [D1RDAGolf] → [Gbgolf] + [D1RDA] + [GaolfGTP];  
 
 irrevreaction_3 [GaolfGDP] + [Gbgolf] → [Golf];  
 
 irrevreaction_4 [GaiGTP] → [GaiGDP];  
 
 irrevreaction_5 [Gbgi] + [GaiGDP] → [Gi];  
 
 irrevreaction_6 [M4RAChGi] → [GaiGTP] + [M4RACh] + [Gbgi];  
 
 irrevreaction_7 [AC5GaolfGTP*ATP] → [cAMP] + [AC5GaolfGTP];  
 
 irrevreaction_8 [cAMP] + [AC5GaolfGTP] → [AC5GaolfGTP*ATP];  
 
 irrevreaction_9 [AC5*ATP] → [cAMP] + [AC5];  
 
 irrevreaction_10 [cAMP] + [AC5] → [AC5*ATP];  
 
 irrevreaction_11 [AC5GaiGTP*ATP] → [cAMP] + [AC5GaiGTP];  
 
 irrevreaction_12 [cAMP] + [AC5GaiGTP] → [AC5GaiGTP*ATP];  
 
 irrevreaction_13 [AC5GaolfGTPGaiGTP*ATP] → [cAMP] + [AC5GaolfGTPGaiGTP];  
 
 irrevreaction_14 [cAMP] + [AC5GaolfGTPGaiGTP] → [AC5GaolfGTPGaiGTP*ATP];  
 
 irrevreaction_15 [AC5CaGaolfGTPGaiGTP*ATP] → [cAMP] + [AC5CaGaolfGTPGaiGTP];  
 
 irrevreaction_16 [cAMP] + [AC5CaGaolfGTPGaiGTP] → [AC5CaGaolfGTPGaiGTP*ATP];  
 
 irrevreaction_17 [AC5CaGaiGTP*ATP] → [cAMP] + [AC5CaGaiGTP];  
 
 irrevreaction_18 [cAMP] + [AC5CaGaiGTP] → [AC5CaGaiGTP*ATP];  
 
 irrevreaction_19 [AC5Ca*ATP] → [cAMP] + [AC5Ca];  
 
 irrevreaction_20 [cAMP] + [AC5Ca] → [AC5Ca*ATP];  
 
 irrevreaction_21 [AC5CaGaolfGTP*ATP] → [cAMP] + [AC5CaGaolfGTP];  
 
 irrevreaction_22 [cAMP] + [AC5CaGaolfGTP] → [AC5CaGaolfGTP*ATP];  
 
 irrevreaction_23 [AC5GaolfGTP] → [AC5] + [GaolfGDP];  
 
 irrevreaction_24 [AC5CaGaolfGTP] → [AC5Ca] + [GaolfGDP];  
 
 irrevreaction_25 [AC5CaGaiGTP] → [AC5Ca] + [GaiGDP];  
 
 irrevreaction_26 [AC5GaiGTP] → [AC5] + [GaiGDP];  
 
 irrevreaction_27 [AC5GaolfGTPGaiGTP] → [AC5GaiGTP] + [GaolfGDP];  
 
 irrevreaction_28 [AC5GaolfGTPGaiGTP] → [AC5GaolfGTP] + [GaiGDP];  
 
 irrevreaction_29 [AC5CaGaolfGTPGaiGTP] → [AC5CaGaiGTP] + [GaolfGDP];  
 
 irrevreaction_30 [AC5CaGaolfGTPGaiGTP] → [AC5CaGaolfGTP] + [GaiGDP];  
 
 irrevreaction_31 [AC5GaolfGTPGaiGTP*ATP] → [GaiGDP] + [AC5GaolfGTP*ATP];  
 
 irrevreaction_32 [AC5GaiGTP*ATP] → [AC5*ATP] + [GaiGDP];  
 
 irrevreaction_33 [AC5GaolfGTPGaiGTP*ATP] → [AC5GaiGTP*ATP] + [GaolfGDP];  
 
 irrevreaction_34 [AC5GaolfGTP*ATP] → [AC5*ATP] + [GaolfGDP];  
 
 irrevreaction_35 [AC5CaGaolfGTP*ATP] → [AC5Ca*ATP] + [GaolfGDP];  
 
 irrevreaction_36 [AC5CaGaolfGTPGaiGTP*ATP] → [AC5CaGaolfGTP*ATP] + [GaiGDP];  
 
 irrevreaction_37 [AC5CaGaiGTP*ATP] → [AC5Ca*ATP] + [GaiGDP];  
 
 irrevreaction_38 [AC5CaGaolfGTPGaiGTP*ATP] → [AC5CaGaiGTP*ATP] + [GaolfGDP];  
 
 irrevreaction_39 [PDE4*cAMP] → [PDE4] + [AMP];  
 
 irrevreaction_40 [PDE10*cAMP] → [PDE10] + [AMP];  
 
 irrevreaction_41 [PDE10c*cAMP] → [PDE10c] + [AMP];  
 
 irrevreaction_42 [PKAc*D32] → [D32p34] + [PKAc];  
 
 irrevreaction_43 [PKAc*B56PP2A] → [B56PP2Ap] + [PKAc];  
 
 irrevreaction_44 [CDK5*D32] → [CDK5] + [D32p75];  
 
 irrevreaction_45 [B56PP2Ap*D32p75] → [B56PP2Ap] + [DARPP32];  
 
 irrevreaction_46 [B72PP2A*D32p75] → [B72PP2A] + [DARPP32];  
 
 irrevreaction_47 [B72PP2ACa*D32p75] → [B72PPA2Ca] + [DARPP32];  
 
 irrevreaction_48 [B56PP2A*D32p75] → [B56PP2A] + [DARPP32];  
 
 irrevreaction_49 [B72PP2ACa*D32p34] → [B72PPA2Ca] + [DARPP32];  
 
 irrevreaction_50 [B72PP2A*D32p34] → [DARPP32] + [B72PP2A];  
 
 irrevreaction_51 [PP2Bc*D32p34] → [DARPP32] + [PP2Bc];  
 
 irrevreaction_52 [B56PP2Ap] → [B56PP2A];  
 
Rules (7)
 
 Assignment Rule (name: totalActivePKA) totalActivePKA = mwcfcf2e7f_907a_4d25_812f_6c10a7293859-mwb320746f_6a8c_4c8b_ae55_23db454339d8
 
 Assignment Rule (name: DApeak) DApeak = 1/(1+exp((-ModelValue_132)*time+ModelValue_132*ModelValue_133))-1/(1+exp((-ModelValue_132)*time+ModelValue_132*(ModelValue_133+ModelValue_134)))
 
 Assignment Rule (name: DApeak_minimum) DApeak_minimum = ModelValue_135
 
 Assignment Rule (name: mwbe974953_e869_4622_b4a8_745555c8d7fd) DA = ModelValue_135+ModelValue_130*(ModelValue_137-ModelValue_136)*DApeak
 
 Assignment Rule (name: AChdip) AChdip = (1-1/(1+exp((-ModelValue_140)*time+ModelValue_140*ModelValue_141)))+1/(1+exp((-ModelValue_140)*time+ModelValue_140*(ModelValue_141+ModelValue_142)))
 
 Assignment Rule (name: AChdip_maximum) AChdip_maximum = ModelValue_143
 
 Assignment Rule (name: mw3e1a2fbf_37b1_490c_9528_6cb6bbf11b21) ACh = (1-ModelValue_138)*ModelValue_143+ModelValue_138*(ModelValue_144+(ModelValue_145-ModelValue_144)*AChdip)
 
 Spine Spatial dimensions: 3.0  Compartment size: 1.0E-15
 
 GaiGTP
Compartment: Spine
Initial concentration: 2.3562470443292
 
 GaolfGDP
Compartment: Spine
Initial concentration: 0.00514744794169027
 
 Gbgolf
Compartment: Spine
Initial concentration: 107.875380092904
 
 GaolfGTP
Compartment: Spine
Initial concentration: 1.13940415390363
 
 D1RDAGolf
Compartment: Spine
Initial concentration: 3.70188602073145
 
 Golf
Compartment: Spine
Initial concentration: 1102.52804493589
 
 D1RGolf
Compartment: Spine
Initial concentration: 785.894688950477
 
 D1RDA
Compartment: Spine
Initial concentration: 16.100094198358
 
 D1R
Compartment: Spine
Initial concentration: 1194.30333083043
 
 cAMP
Compartment: Spine
Initial concentration: 91.6467576551524
 
 Ca
Compartment: Spine
Initial concentration: 60.0
Constant
 
 AC5
Compartment: Spine
Initial concentration: 0.507493613791483
 
 AC5GaolfGTP
Compartment: Spine
Initial concentration: 0.397626017086897
 
 CaM
Compartment: Spine
Initial concentration: 7686.15789228991
 
 CaMCa2
Compartment: Spine
Initial concentration: 316.776054644554
 
 CaMCa4
Compartment: Spine
Initial concentration: 2.47080976475754
 
 PDE4
Compartment: Spine
Initial concentration: 1531.9927671361
 
 PKA
Compartment: Spine
Initial concentration: 1100.85005741739
 
 PKAcAMP2
Compartment: Spine
Initial concentration: 26.2312279909643
 
 PKAcAMP4
Compartment: Spine
Initial concentration: 0.831786420159049
 
 PKAreg
Compartment: Spine
Initial concentration: 72.0869281714876
 
 PKAc
Compartment: Spine
Initial concentration: 11.5386581348021
 
 PP2B
Compartment: Spine
Initial concentration: 5.40475669921873
 
 PP2Bc
Compartment: Spine
Initial concentration: 194.502520839594
 
 PP2BCaM
Compartment: Spine
Initial concentration: 1380.87227011886
 
 PP2BCaMCa2
Compartment: Spine
Initial concentration: 419.196440881025
 
 DARPP32
Compartment: Spine
Initial concentration: 37271.6543135964
 
 PKAc*D32
Compartment: Spine
Initial concentration: 7.16774795405187
 
 D32p34
Compartment: Spine
Initial concentration: 0.678978545756906
 
 B72PP2A
Compartment: Spine
Initial concentration: 860.232017549719
 
 PKAc*B56PP2A
Compartment: Spine
Initial concentration: 16.40971542072
 
 B56PP2Ap
Compartment: Spine
Initial concentration: 410.242885172213
 
 CDK5
Compartment: Spine
Initial concentration: 233.496415726183
 
 PP1
Compartment: Spine
Initial concentration: 1493.10639547125
 
 CDK5*D32
Compartment: Spine
Initial concentration: 1566.50358427382
 
 D32p75
Compartment: Spine
Initial concentration: 8659.68104422894
 
 PKAcD32p75
Compartment: Spine
Initial concentration: 36.9708066619157
 
 B72PPA2Ca
Compartment: Spine
Initial concentration: 51.6139210529853
 
 B56PP2Ap*D32p75
Compartment: Spine
Initial concentration: 296.047711354635
 
 B72PP2A*D32p75
Compartment: Spine
Initial concentration: 805.333502271791
 
 B72PP2ACa*D32p75
Compartment: Spine
Initial concentration: 44.6960093760864
 
 PP1D32p34
Compartment: Spine
Initial concentration: 506.893604528755
 
 PP2Bc*D32p34
Compartment: Spine
Initial concentration: 0.0240114612997978
 
 B72PP2A*D32p34
Compartment: Spine
Initial concentration: 224.645801649792
 
  DA
Compartment: Spine
Initial concentration: 10.0
 
 AMP
Compartment: Spine
Initial concentration: 0.0
Constant
 
 AC5Ca
Compartment: Spine
Initial concentration: 0.0338357229453947
 
 AC5CaGaolfGTP
Compartment: Spine
Initial concentration: 0.0265277448296902
 
 AC5GaiGTP
Compartment: Spine
Initial concentration: 1.70785338199615
 
 AC5CaGaiGTP
Compartment: Spine
Initial concentration: 0.113888299015711
 
 B56PP2A
Compartment: Spine
Initial concentration: 711.07555205532
 
 B56PP2A*D32p75
Compartment: Spine
Initial concentration: 566.224135997113
 
 B72PP2ACa*D32p34
Compartment: Spine
Initial concentration: 13.4787480996268
 
 PDE4*cAMP
Compartment: Spine
Initial concentration: 468.007232863897
 
 AC5GaolfGTPGaiGTP
Compartment: Spine
Initial concentration: 4.39135728748305E-4
 
 AC5CaGaolfGTPGaiGTP
Compartment: Spine
Initial concentration: 2.92811632030252E-5
 
 M4R
Compartment: Spine
Initial concentration: 1529.69994816436
 
 M4RACh
Compartment: Spine
Initial concentration: 25.650119219421
 
 M4RGi
Compartment: Spine
Initial concentration: 214.722656407666
 
 Gi
Compartment: Spine
Initial concentration: 1095.19571044122
 
 M4RAChGi
Compartment: Spine
Initial concentration: 229.927276208549
 
 Gbgi
Compartment: Spine
Initial concentration: 460.154356942568
 
 GaiGDP
Compartment: Spine
Initial concentration: 0.299804540897635
 
  ACh
Compartment: Spine
Initial concentration: 100.0
 
 PDE10c
Compartment: Spine
Initial concentration: 0.230445425050315
 
 PDE10
Compartment: Spine
Initial concentration: 246.931440841991
 
 PDE10*cAMP
Compartment: Spine
Initial concentration: 452.609318325671
 
 PDE10c*cAMP
Compartment: Spine
Initial concentration: 0.228795407287519
 
 ATP
Compartment: Spine
Initial concentration: 5000000.0
Constant
 
 AC5GaolfGTPGaiGTP*ATP
Compartment: Spine
Initial concentration: 0.109825804214832
 
 AC5GaiGTP*ATP
Compartment: Spine
Initial concentration: 427.086542949603
 
 AC5GaolfGTP*ATP
Compartment: Spine
Initial concentration: 99.5522607546951
 
 AC5*ATP
Compartment: Spine
Initial concentration: 126.887958343277
 
 AC5CaGaolfGTP*ATP
Compartment: Spine
Initial concentration: 6.63679803850652
 
 AC5CaGaiGTP*ATP
Compartment: Spine
Initial concentration: 28.4724047907866
 
 AC5CaGaolfGTPGaiGTP*ATP
Compartment: Spine
Initial concentration: 0.00732171483303589
 
 AC5Ca*ATP
Compartment: Spine
Initial concentration: 8.459194407526
 
 PP1*AKAR3p
Compartment: Spine
Initial concentration: 0.0
 
 PKAc*AKAR3
Compartment: Spine
Initial concentration: 0.0
 
  totalActivePKA
Compartment: Spine
Initial concentration: 35.1161215095719
 
Global Parameters (160)
 
   krM4R*Gi
Value: 90.0
Constant
 
   kfM4R*Gi
Value: 0.012
Constant
 
   krPP2B*CaMCa2
Value: 3.0
Constant
 
   kfPP2B*CaMCa2
Value: 1.0
Constant
 
   krPP2BCaMCa2*2Ca
Value: 10.0
Constant
 
   kfPP2BCaMCa2*2Ca
Value: 0.1
Constant
 
   krPP2BCaM*2Ca
Value: 0.91
Constant
 
   kfPP2BCaM*2Ca
Value: 0.006
Constant
 
   kfPP1*D32p34
Value: 0.04
Constant
 
   krPP1*D32p34
Value: 0.08
Constant
 
   kfPP2B*CaMCa4
Value: 1.0
Constant
 
   krPP2B*CaMCa4
Value: 3.0
Constant
 
   kfB72PP2A*Ca
Value: 1.0E-4
Constant
 
   krB72PP2A*Ca
Value: 0.1
Constant
 
   kfPP2B*CaM
Value: 1.0
Constant
 
   krPP2B*CaM
Value: 30.0
Constant
 
   kcatPKAc*D32
Value: 10.0
Constant
 
   kGaolfGTPase
Value: 30.0
Constant
 
   kfPP2Bc*D32p34
Value: 0.002
Constant
 
   krPP2Bc*D32p34
Value: 1.0
Constant
 
   kfB56PP2A*D32p75
Value: 8.0E-4
Constant
 
   krB56PP2A*D32p75
Value: 6.4
Constant
 
   kfB56PP2Ap*D32p75
Value: 0.0015
Constant
 
   krB56PP2Ap*D32p75
Value: 10.0
Constant
 
   kcatB56PP2Ap*D32p75
Value: 8.0
Constant
 
   kcatB56PP2A*D32p75
Value: 2.3
Constant
 
   kcatB72PP2ACa*D32p75
Value: 5.0
Constant
 
   kcatB72PP2A*D32p75
Value: 1.0
Constant
 
   kfB72PP2A*D32p75
Value: 8.0E-4
Constant
 
   krB72PP2A*D32p75
Value: 6.4
Constant
 
   kfB72PP2ACa*D32p75
Value: 0.0015
Constant
 
   krB72PP2ACa*D32p75
Value: 10.0
Constant
 
   kcatPP2Bc*D32p34
Value: 10.0
Constant
 
   kcatCDK5*D32
Value: 3.0
Constant
 
   kactGi
Value: 60.0
Constant
 
   kGiGTPase
Value: 30.0
Constant
 
   kGiback
Value: 100.0
Constant
 
   kfM4RACh*Gi
Value: 1.2
Constant
 
   krM4RACh*Gi
Value: 90.0
Constant
 
   kfPKA*2cAMP
Value: 2.6E-4
Constant
 
   krPKA*2cAMP
Value: 1.0
Constant
 
   krPKAc*PKAr
Value: 10.0
Constant
 
   kfPKAc*PKAr
Value: 0.01
Constant
 
   kfPKA2cAMP*2cAMP
Value: 3.46E-4
Constant
 
   krPKA2cAMP*2cAMP
Value: 1.0
Constant
 
   kfCDK5*D32
Value: 9.0E-4
Constant
 
   krCDK5*D32
Value: 2.0
Constant
 
   kactGolf
Value: 15.0
Constant
 
   kcatPDE4*cAMP
Value: 2.0
Constant
 
   kfPKAc*D32
Value: 3.0E-4
Constant
 
   krPKAc*D32
Value: 8.0
Constant
 
   kfPDE4*cAMP
Value: 0.01
Constant
 
   krPDE4*cAMP
Value: 1.0
Constant
 
   krPDE10*cAMP
Value: 9.0
Constant
 
   kcatPDE10c*cAMP
Value: 10.0
Constant
 
   kfPDE10*cAMP
Value: 1.0E-6
Constant
 
   kfcAMP*PDE10
Value: 0.1
Constant
 
   krcAMP*PDE10
Value: 2.0
Constant
 
   kcatcAMP*PDE10
Value: 3.0
Constant
 
   kcatAC5GaolfGTP*ATP
Value: 20.0
Constant
 
   kicatAC5GaolfGTP*ATP
Value: 0.084
Constant
 
   kcatAC5*ATP
Value: 1.0
Constant
 
   kicatAC5*ATP
Value: 4.0E-4
Constant
 
   kcatAC5GaiGTP*ATP
Value: 0.25
Constant
 
   kicatAC5GaiGTP*ATP
Value: 0.00105
Constant
 
   kcatAC5CaGaiGTP*ATP
Value: 0.125
Constant
 
   kicatAC5CaGaiGTP*ATP
Value: 2.8125E-5
Constant
 
   kcatAC5Ca*ATP
Value: 0.5
Constant
 
   kicatAC5Ca*ATP
Value: 1.5E-4
Constant
 
   kcatAC5CaGaolfGTP*ATP
Value: 10.0
Constant
 
   kicatAC5CaGaolfGTP*ATP
Value: 0.022
Constant
 
   kfM4R*ACh
Value: 0.01
Constant
 
   kfM4RGi*ACh
Value: 1.0
Constant
 
   krM4RGi*ACh
Value: 90.0
Constant
 
   krM4R*ACh
Value: 90.0
Constant
 
   kcatAC5GaolfGTPGaiGTP*ATP
Value: 5.0
Constant
 
   kicatAC5GaolfGTPGaiGTP*ATP
Value: 0.006
Constant
 
   kicatAC5CaGaolfGTPGaiGTP*ATP
Value: 0.00175
Constant
 
   kcatAC5CaGaolfGTPGaiGTP*ATP
Value: 2.5
Constant
 
   kfAC5*ATP
Value: 1.0E-4
Constant
 
   kfAC5CaGaolfGTP*ATP
Value: 5.5E-4
Constant
 
   kfAC5CaGaiGTP*ATP
Value: 5.625E-5
Constant
 
   kfAC5CaGaolfGTPGaiGTP*ATP
Value: 1.75E-4
Constant
 
   kfCaM*2Ca
Value: 0.006
Constant
 
   kGolfback
Value: 100.0
Constant
 
   krCaM*2Ca
Value: 9.1
Constant
 
   kdpB56PP2Ap
Value: 0.008
Constant
 
   krCaMCa2*2Ca
Value: 1000.0
Constant
 
   krPKAc*D32p75
Value: 1.0
Constant
 
   kfPKAc*B56PP2A
Value: 0.001
Constant
 
   krPKAc*B56PP2A
Value: 0.3
Constant
 
   kfCaMCa2*2Ca
Value: 0.1
Constant
 
   kcatPKAc*B56PP2A
Value: 0.2
Constant
 
   kfPKAc*D32p75
Value: 3.7E-4
Constant
 
   kfAC5GaolfGTP*ATP
Value: 0.00105
Constant
 
   kfAC5GaiGTP*ATP
Value: 6.25E-5
Constant
 
   kfAC5GaolfGTPGaiGTP*ATP
Value: 3.0E-4
Constant
 
   kfAC5Ca*ATP
Value: 7.5E-5
Constant
 
   kfD1R*Golf
Value: 0.003
Constant
 
   krD1R*Golf
Value: 5.0
Constant
 
   kfD1RDA*Golf
Value: 0.003
Constant
 
   krD1RDA*Golf
Value: 5.0
Constant
 
   kfB72PP2A*D32p34
Value: 0.5
Constant
 
   krB72PP2A*D32p34
Value: 1.0
Constant
 
   krAC5X*ATP
Value: 1.0
Constant
 
   kcatB72PP2A*D32p34
Value: 0.3
Constant
 
   kfAC5XGaolfGTP
Value: 0.2
Constant
 
   kfAC5Ca
Value: 0.001
Constant
 
   kfAC5XGaiGTP
Value: 50.0
Constant
 
   kfAC5XNCGaiGTP
Value: 0.01
Constant
 
   kfAC5XNCGaolfGTP
Value: 0.002
Constant
 
   krAC5XGaolfGTP
Value: 0.1
Constant
 
   krAC5Ca
Value: 0.9
Constant
 
   krAC5XGaiGTP
Value: 5.0
Constant
 
   krAC5XNCGaiGTP
Value: 0.01
Constant
 
   krAC5XNCGaolfGTP
Value: 0.01
Constant
 
   krgso
Value: 0.2
Constant
 
   krgsi
Value: 30.0
Constant
 
   kcatPP1*AKAR3p
Value: 1.2
Constant
 
   kfPP1*AKAR3p
Constant
 
   krPP1*AKAR3p
Value: 10.0
Constant
 
   kcatPKAc*AKAR3
Value: 3.0
Constant
 
   kfPKAc*AKAR3
Constant
 
   krPKAc*AKAR3
Value: 1.0
Constant
 
   kfPDE10c*cAMP
Value: 0.13
Constant
 
   krPDE10c*cAMP
Value: 2.0
Constant
 
   kfD1R*DA
Value: 0.005
Constant
 
   kfD1RGolf*DA
Value: 0.005
Constant
 
   krD1R*DA
Value: 5.0
Constant
 
   krD1RGolf*DA
Value: 5.0
Constant
 
   DApeak_present
Constant
 
  DApeak
Value: 1.38389652673674E-87
 
   DApeak_steepness
Value: 100.0
Constant
 
   DApeak_startTime
Value: 2.0
Constant
 
   DApeak_duration
Value: 1.0
Constant
 
   DAbasal
Value: 10.0
Constant
 
  DApeak_minimum
Value: 10.0
 
   DApeak_maximum
Value: 1500.0
Constant
 
   AChdip_present
Constant
 
  AChdip
Value: 1.0
 
   AChdip_steepness
Value: 100.0
Constant
 
 AChdip_startTime
Value: 2.0
Constant
 
   AChdip_duration
Value: 0.4
Constant
 
   AChbasal
Value: 100.0
Constant
 
 AChdip_minimum
Value: 0.001
Constant
 
  AChdip_maximum
Value: 100.0
 
 Initial for AChbasal
Value: 100.0
Constant
 
 Initial for AChdip_duration
Value: 0.4
Constant
 
 Initial for AChdip_maximum
Value: 100.0
Constant
 
 Initial for AChdip_minimum
Value: 0.001
Constant
 
 Initial for AChdip_present
Constant
 
 Initial for AChdip_startTime
Value: 2.0
Constant
 
 Initial for AChdip_steepness
Value: 100.0
Constant
 
 Initial for DAbasal
Value: 10.0
Constant
 
 Initial for DApeak_duration
Value: 1.0
Constant
 
 Initial for DApeak_maximum
Value: 1500.0
Constant
 
 Initial for DApeak_minimum
Value: 10.0
Constant
 
 Initial for DApeak_present
Constant
 
 Initial for DApeak_startTime
Value: 2.0
Constant
 
 Initial for DApeak_steepness
Value: 100.0
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000635

Curator's comment: (updated: 02 May 2017 16:29:05 BST)

We reproduce Figure 3B using COPASI and used Matplotlib to generate the plot.

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