Name
Title | ||
|---|---|---|
A kinetic mechanism for nicotinic acetylcholine receptors based on multiple allosteric transitions. |
Abstract | ||
|---|---|---|
Nicotinic acetylcholine receptors are trans- membrane oligomeric proteins that mediate interconver- sions between open and closed channel states under the control of neurotransmitters. Fast in vitro chemical ki- netics 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 aƒnities 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 hy- pothetical linear reaction coordinate. Application of the model to the peripheral nicotinic acetylcholine receptor (nAChR) accounts for the main properties of ligand-gat- ing, 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 K $ in the 50 nM range, hence some 140-fold stronger than the apparent aƒnity 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 path- way, as assumed in the standard 'cyclic' model. Tran- |
Year | DOI | Venue |
|---|---|---|
1996 | 10.1007/s004220050302 | Biological Cybernetics |
Keywords | Field | DocType |
kinetics,resting state,transition state,dose response | Nanotechnology,Cooperativity,Biophysics,Control theory,Nicotinic agonist,Allosteric regulation,Transition state,Acetylcholine receptor,Nicotinic acetylcholine receptor,Coincidence detection in neurobiology,Mathematics,Reaction coordinate | Journal |
Volume | Issue | ISSN |
75 | 5 | 0340-1200 |
Citations | PageRank | References |
7 | 2.20 | 4 |
Authors | ||
5 | ||
Name | Order | Citations | PageRank |
|---|---|---|---|
| Stuart J Edelstein | 1 | 12 | 3.49 |
| O Schaad | 2 | 14 | 3.92 |
| Eric Henry | 3 | 7 | 2.20 |
| Daniel Bertrand | 4 | 17 | 3.09 |
| Jean-pierre Changeux | 5 | 52 | 8.44 |