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:
+ + +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.
+This model is hosted on + BioModels Database + and identified by: + BIOMD0000000001.
+To cite BioModels Database, please use: + BioModels Database: + An enhanced, curated and annotated resource for published + quantitative kinetic models.
+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.
+biliganded basal state
+ +monoliganded intermediate
+ +monoliganded active state
+ +unkiganded active state
+ +monoliganded basal state
+ +unliganded basal state
+ +biliganded desensitised state
+ +fully desensitised state
+ +biliganded intermediate
+ +monoliganded desensitised state
+ +unliganted intermediate
+ +biliganted active state
+ +first ligand on basal
+ +kf_0 * B - kr_0 * BL
+ +second ligand on basal
+ +kf_1 * BL - kr_1 * BLL
+ +opening of biliganded
+ +kf_2 * BLL - kr_2 * ALL
+ +first ligand on active
+ +kf_3 * A - kr_3 * AL
+ +second ligand on active
+ +kf_4 * AL - kr_4 * ALL
+ +opening of unliganded
+ +kf_5 * B - kr_5 * A
+ +opening of monoliganded
+ +kf_6 * BL - kr_6 * AL
+ +first ligand on intermediate
+ +kf_7 * I - kr_7 * IL
+ +second ligand on intermediate
+ +kf_8 * IL - kr_8 * ILL
+ +unliganded active <=> unliganded intermediate
+ +kf_9 * A - kr_9 * I
+ +monoliganded active <=> monoliganded intermediate
+ +kf_10 * AL - kr_10 * IL
+ +biliganded active <=> biliganded intermediate
+ +kf_11 * ALL - kr_11 * ILL
+ +first ligand on desensitised
+ +kf_12 * D - kr_12 * DL
+ +second ligand on desensitised
+ +kf_13 * DL - kr_13 * DLL
+ +unliganded intermediate <=> unliganded desensitised
+ +kf_14 * I - kr_14 * D
+ +monoliganded intermediate <=> monoliganded desensitised
+ +kf_15 * IL - kr_15 * DL
+ +biliganded intermediate <=> biliganded desensitised
+ +kf_16 * ILL - kr_16 * DLL
+ +