Short description
Edelstein1996 - EPSP ACh event

Model of a nicotinic Excitatory Post-Synaptic Potential in a Torpedo electric organ. Acetylcholine is not represented explicitely, but by an event that changes the constants of transition from unliganded to liganded. 

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): 361-379

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.

Format
SBML (L2V4)
Related Publication
  • A kinetic mechanism for nicotinic acetylcholine receptors based on multiple allosteric transitions.
  • Edelstein SJ, Schaad O, Henry E, Bertrand D, Changeux JP
  • Biological cybernetics , 11/ 1996 , Volume 75 , pages: 361-379
  • Département de Biochimie, Université de Geneve, Switzerland. Stuart.Edelstein@biochem.unige.ch
  • 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.
Contributors
Nicolas Le Novère

Metadata information

is
BioModels Database MODEL6613849442
BioModels Database BIOMD0000000001
isDescribedBy
PubMed 8983160
hasTaxon
Curation status
Curated
Name Description Size Actions

Model file

BIOMD0000000001_url.xml SBML L2V4 representation of Edelstein1996 - EPSP ACh event 49.66 KB Preview | Download

Additional files

BIOMD0000000001.vcml Auto-generated VCML file 65.46 KB Preview | Download
BIOMD0000000001_urn.xml Auto-generated SBML file with URNs 49.25 KB Preview | Download
BIOMD0000000001_manual.png Manually generated Reaction graph (PNG) 47.33 KB Preview | Download
BIOMD0000000001.xpp Auto-generated XPP file 5.94 KB Preview | Download
BIOMD0000000001.svg Auto-generated Reaction graph (SVG) 37.25 KB Preview | Download
BIOMD0000000001.m Auto-generated Octave file 8.87 KB Preview | Download
BIOMD0000000001_manual.svg Manually generated Reaction graph (SVG) 37.25 KB Preview | Download
BIOMD0000000001-biopax3.owl Auto-generated BioPAX (Level 3) 36.80 KB Preview | Download
BIOMD0000000001-biopax2.owl Auto-generated BioPAX (Level 2) 23.08 KB Preview | Download
BIOMD0000000001.png Auto-generated Reaction graph (PNG) 47.33 KB Preview | Download
BIOMD0000000001.pdf Auto-generated PDF file 219.76 KB Preview | Download
BIOMD0000000001.sci Auto-generated Scilab file 67.00 bytes Preview | Download

  • Model originally submitted by : Nicolas Le Novère
  • Submitted: 13-Sep-2005 13:18:50
  • Last Modified: 19-May-2017 15:33:51
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 19-May-2017 15:33:51
    • Submitted by: Nicolas Le Novère
    • With comment: Current version of Edelstein1996 - EPSP ACh event
  • Version: 1 public model Download this version
    • Submitted on: 13-Sep-2005 13:18:50
    • Submitted by: Nicolas Le Novère
    • With comment: Original import of Edelstein1996_EPSP_AChEvent
Curator's comment:
(added: 19 May 2017, 15:33:27, updated: 19 May 2017, 15:33:27)
Recalculations of the time courses shown in figures 4 b and c of the original publication. The simulations were performed with Copasi 4.5.31 (development) and the results plotted with GNUplot. For 4b the event trigger time, t2, was changed to > 100. For figure 4c, t2, the time point of ligand removal, was left at 20 sec. The time axis in 4c starts directly after ligand removal.