AGONIST SELF-INHIBITORY BINDING-SITE OF THE NICOTINIC ACETYLCHOLINE-RECEPTOR

A major focus of current research on the nicotinic acetylcholine recep tor (AChR) has been to understand the molecular mechanism of ion chann el inhibition. In particular, we put special emphasis on the descripti on of the localization of the agonist self-inhibitory binding site. Bi nding of agonist in the millimolar concentration range to this particu lar site produces inhibition of the ion flux activity previously elici ted by the same agonist at micromolar concentrations. Due to the simil itude in the pharmacological and electrophysiological behavior in inhi biting the ion channel of both high agonist concentrations and noncomp etitive antagonists, we first describe the localization of noncompetit ive inhibitor binding sites on the AChR. There is a great body of expe rimental evidence for the existence and location of luminal high-affin ity noncompetitive inhibitor binding sites. In this regard, the most s imple mechanism to describe the action of noncompetitive inhibitors wh ich bind to luminal sites and, by its semblance, the agonist self-inhi bition itself, is based on the assumption that these compounds enter t he open channel, bind to different rings within the M2 transmembrane d omain of the receptor, and block cation flux by occluding the receptor pore. However, the existence of high-affinity nonluminal noncompetiti ve inhibitor binding sites is not consistent with the open-channel-blo cking mechanism. Instead, the presence of the quinacrine locus at the lipid-protein (alpha M1) interface similar to 7 Angstrom from the lipi d-water interface and the ethidium domain located similar to 46 Angstr om from the membrane surface in the wall of the vestibule open the pos sibility for the regulation of cation permeation by an allosteric proc ess. Additionally, the observed (at least partially) overlapping betwe en the quinacrine and the agonist self-inhibitory binding site also su ggests an allosteric process for agonist self-inhibition. For this alt ernative mechanism, cholinergic agonist molecules first need to be par titioned into (or to be adsorbed onto) the lipid membrane to further i nteract with its binding site located at the lipid-protein interface. (C) 1996 Wiley-Liss, Inc.