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J. Biol. Chem., Vol. 275, Issue 39, 30196-30201, September 29, 2000

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Binding Properties of Agonists and Antagonists to Distinct Allosteric States of the Nicotinic Acetylcholine Receptor Are Incompatible with a Concerted Model^*

Michael Krauss, Daniel Korr, Andreas Herrmann^§, and Ferdinand Hucho^¶

From  AG Neurochemie, Institut für Biochemie, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany and the ^§ Institut für Biologie/Biophysik, Humboldt-Universität Berlin, Invalidenstrasse 43, 10115 Berlin, Germany

Recent work has shown that the nicotinic acetylcholine receptor (nAChR) can be fixed in distinct conformations by chemical cross-linking with glutardialdehyde, which abolishes allosteric transitions in the protein. Here, two conformations that resemble the desensitized and the resting states were compared with respect to their affinities for different classes of ligands. The same ligands were tested for their ability to convert the nAChR from a conformation with low affinity to a conformation with high affinity for acetylcholine. As expected, agonists were found to bind with higher affinity to the desensitized state-like conformation and to induce a shift of the nAChR to this high affinity state. In contrast, although most antagonists tested bound preferentially to the desensitized receptor as well they failed to induce a change of the affinity for acetylcholine. These observations sharply contradict basic predictions of the concerted model, including the postulate of a preformed equilibrium between the different states of the nAChR in the absence of agonist. With a similar approach we could show that the non-competitive inhibitor ethidium is displaced in a non-allosteric manner by other well characterized channel blockers from the cross-linked nAChR. These results require revision of current models for the mechanisms underlying non-competitive antagonism at the nAChR.

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