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BIOMD0000000002 - Edelstein1996 - EPSP ACh species

 

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Reference Publication
Publication ID: 8983160
Edelstein SJ, Schaad O, Henry E, Bertrand D, Changeux JP.
A kinetic mechanism for nicotinic acetylcholine receptors based on multiple allosteric transitions.
Biol Cybern 1996 Nov; 75(5): 361-379
Département de Biochimie, Université de Geneve, Switzerland. Stuart.Edelstein@biochem.unige.ch  [more]
Model
Original Model: BIOMD0000000002.xml.origin
Submitter: Nicolas Le Novère
Submission ID: MODEL6614086398
Submission Date: 13 Sep 2005 12:23:07 UTC
Last Modification Date: 01 Apr 2014 17:42:27 UTC
Creation Date: 02 Feb 2005 14:41:42 UTC
Encoders:  Nicolas Le Novère
set #1
bqbiol:isVersionOf Gene Ontology transmission of nerve impulse
Gene Ontology cell surface receptor signaling pathway
Gene Ontology neuromuscular synaptic transmission
bqbiol:hasTaxon Taxonomy Torpedo californica
Notes
Edelstein1996 - EPSP ACh species

Model of a nicotinic Excitatory Post-Synaptic Potential in a Torpedo electric organ. Acetylcholine is represented explicitely as a molecular species.

This model has initially been encoded using StochSim.

This model is described in the article:

Edelstein SJ, Schaad O, Henry E, Bertrand D, Changeux JP.
Biol. Cybern. 1996 Nov; 75(5):361-79

Abstract:

Nicotinic acetylcholine receptors are transmembrane oligomeric proteins that mediate interconversions between open and closed channel states under the control of neurotransmitters. Fast in vitro chemical kinetics and in vivo electrophysiological recordings are consistent with the following multi-step scheme. Upon binding of agonists, receptor molecules in the closed but activatable resting state (the Basal state, B) undergo rapid transitions to states of higher affinities with either open channels (the Active state, A) or closed channels (the initial Inactivatable and fully Desensitized states, I and D). In order to represent the functional properties of such receptors, we have developed a kinetic model that links conformational interconversion rates to agonist binding and extends the general principles of the Monod-Wyman-Changeux model of allosteric transitions. The crucial assumption is that the linkage is controlled by the position of the interconversion transition states on a hypothetical linear reaction coordinate. Application of the model to the peripheral nicotine acetylcholine receptor (nAChR) accounts for the main properties of ligand-gating, including single-channel events, and several new relationships are predicted. Kinetic simulations reveal errors inherent in using the dose-response analysis, but justify its application under defined conditions. The model predicts that (in order to overcome the intrinsic stability of the B state and to produce the appropriate cooperativity) channel activation is driven by an A state with a Kd in the 50 nM range, hence some 140-fold stronger than the apparent affinity of the open state deduced previously. According to the model, recovery from the desensitized states may occur via rapid transit through the A state with minimal channel opening, thus without necessarily undergoing a distinct recovery pathway, as assumed in the standard 'cycle' model. Transitions to the desensitized states by low concentration 'pre-pulses' are predicted to occur without significant channel opening, but equilibrium values of IC50 can be obtained only with long pre-pulse times. Predictions are also made concerning allosteric effectors and their possible role in coincidence detection. In terms of future developments, the analysis presented here provides a physical basis for constructing more biologically realistic models of synaptic modulation that may be applied to artificial neural networks.

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: 8983160 Submission Date: 13 Sep 2005 12:23:07 UTC Last Modification Date: 01 Apr 2014 17:42:27 UTC Creation Date: 02 Feb 2005 14:41:42 UTC
Mathematical expressions
Reactions
React0 React1 React2 React3
React4 React5 React6 React7
React8 React9 React10 React11
React12 React13 React14 React15
React16      
Physical entities
Compartments Species
compartment1 BasalACh2 IntermediateACh ActiveACh
Active BasalACh Basal
DesensitisedACh2 Desensitised IntermediateACh2
DesensitisedACh Intermediate ActiveACh2
ACh    
Global parameters
kf_0 kr_0 kf_1 kr_1
kf_2 kr_2 kf_3 kr_3
kf_4 kr_4 kf_5 kr_5
kf_6 kr_6 kf_7 kr_7
kf_8 kr_8 kf_9 kr_9
kf_10 kr_10 kf_11 kr_11
kf_12 kr_12 kf_13 kr_13
kf_14 kr_14 kf_15 kr_15
kf_16 kr_16    
Reactions (17)
 
 React0 [Basal] + [ACh] ↔ [BasalACh];  
 
 React1 [BasalACh] + [ACh] ↔ [BasalACh2];  
 
 React2 [BasalACh2] ↔ [ActiveACh2];  
 
 React3 [Active] + [ACh] ↔ [ActiveACh];  
 
 React4 [ActiveACh] + [ACh] ↔ [ActiveACh2];  
 
 React5 [Basal] ↔ [Active];  
 
 React6 [BasalACh] ↔ [ActiveACh];  
 
 React7 [Intermediate] + [ACh] ↔ [IntermediateACh];  
 
 React8 [IntermediateACh] + [ACh] ↔ [IntermediateACh2];  
 
 React9 [Active] ↔ [Intermediate];  
 
 React10 [ActiveACh] ↔ [IntermediateACh];  
 
 React11 [ActiveACh2] ↔ [IntermediateACh2];  
 
 React12 [Desensitised] + [ACh] ↔ [DesensitisedACh];  
 
 React13 [DesensitisedACh] + [ACh] ↔ [DesensitisedACh2];  
 
 React14 [Intermediate] ↔ [Desensitised];  
 
 React15 [IntermediateACh] ↔ [DesensitisedACh];  
 
 React16 [IntermediateACh2] ↔ [DesensitisedACh2];  
 
 compartment1 Spatial dimensions: 3.0  Compartment size: 1.0E-16
 
 BasalACh2
Compartment: compartment1
Initial amount: 0.0
 
 IntermediateACh
Compartment: compartment1
Initial amount: 0.0
 
 ActiveACh
Compartment: compartment1
Initial amount: 0.0
 
 Active
Compartment: compartment1
Initial amount: 0.0
 
 BasalACh
Compartment: compartment1
Initial amount: 0.0
 
 Basal
Compartment: compartment1
Initial amount: 1.0E-22
 
 DesensitisedACh2
Compartment: compartment1
Initial amount: 0.0
 
 Desensitised
Compartment: compartment1
Initial amount: 0.0
 
 IntermediateACh2
Compartment: compartment1
Initial amount: 0.0
 
 DesensitisedACh
Compartment: compartment1
Initial amount: 0.0
 
 Intermediate
Compartment: compartment1
Initial amount: 0.0
 
 ActiveACh2
Compartment: compartment1
Initial amount: 0.0
 
 ACh
Compartment: compartment1
Initial amount: 1.0E-21
 
Global Parameters (34)
 
   kf_0
Value: 3.0E8
Constant
 
   kr_0
Value: 8000.0
Constant
 
   kf_1
Value: 1.5E8
Constant
 
   kr_1
Value: 16000.0
Constant
 
   kf_2
Value: 30000.0
Constant
 
   kr_2
Value: 700.0
Constant
 
   kf_3
Value: 3.0E8
Constant
 
   kr_3
Value: 8.64
Constant
 
   kf_4
Value: 1.5E8
Constant
 
   kr_4
Value: 17.28
Constant
 
   kf_5
Value: 0.54
Constant
 
   kr_5
Value: 10800.0
Constant
 
   kf_6
Value: 130.0
Constant
 
   kr_6
Value: 2740.0
Constant
 
   kf_7
Value: 3.0E8
Constant
 
   kr_7
Value: 4.0
Constant
 
   kf_8
Value: 1.5E8
Constant
 
   kr_8
Value: 8.0
Constant
 
   kf_9
Value: 19.7
Constant
 
   kr_9
Value: 3.74
Constant
 
   kf_10
Value: 19.85
Constant
 
   kr_10
Value: 1.74
Constant
 
   kf_11
Value: 20.0
Constant
 
   kr_11
Value: 0.81
Constant
 
   kf_12
Value: 3.0E8
Constant
 
   kr_12
Value: 4.0
Constant
 
   kf_13
Value: 1.5E8
Constant
 
   kr_13
Value: 8.0
Constant
 
   kf_14
Value: 0.05
Constant
 
   kr_14
Value: 0.0012
Constant
 
   kf_15
Value: 0.05
Constant
 
   kr_15
Value: 0.0012
Constant
 
   kf_16
Value: 0.05
Constant
 
   kr_16
Value: 0.0012
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000002

Curator's comment: (updated: 21 Oct 2010 15:01:54 BST)

Recalculations of the time courses shown in figures 4b of the original publication. The simulation was performed with Copasi 4.6.32.

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