Acetylcholine Receptor: An Allosteric Protein

Abstract

The nicotine receptor for the neurotransmitter acetylcholine is an allosteric protein composed of four different subunits assembled in a transmembrane pentamer alpha 2 beta gamma delta. The protein carries two acetylcholine sites at the level of the alpha subunits and contains the ion channel. The complete sequence of the four subunits is known. The membrane-bound protein undergoes conformational transitions that regulate the opening of the ion channel and are affected by various categories of pharmacologically active ligands.

Desensitization of neuronal nicotinic receptors

“…Rapid biochemical kinetic studies (Heidmann and Changeux, 1979;Neubig et al, 1982) also support the two-state model of desensitization, and affinities of the three states (R, I, and D) have been estimated from the concentration-dependence of the measured transitions (for review see Galzi and Changeux, 1995). Thus, for muscle nAChRs at equilibrium, which presumably reflects agonist stabilization of the D state, the affinity for ACh is Ϸ1 nM, whereas the equilibrium constant for the intermediate I state is Ϸ1 M (Changeux et al, 1984). Interestingly, these two values are quite similar to the two affinities estimated from [ 3 H]nicotine binding to high affinity sites in brain (Lippiello et al, 1987;see below).…”

“…Then depending on their relative affinities for each conformation [e.g., K 0 and K 1 in Fig. 2(A)], agonists will preferentially stabilize one or more of the states (Changeux et al, 1984;Buisson and Bertrand, 1998). Following exposure to agonist, the time course of desensitization will be governed by the transition rate constants [e.g., D 3 R in Fig.…”

“…Each of the four states can bind multiple (two or more) molecules of agonist (states not shown). Modified from Changeux et al, (1984). thus their original model of channel binding and gating has now been extended to take into account this now well-established property [see e.g., Feltz and Trautmann, 1982; Fig.…”

“…In addition, an intermediate desensitized state (I) has been added for both muscle and neuronal nAChRs in order to reflect the biexponential time course of desensitization onset and recovery [ Fig. 2(B,C); Feltz and Trautmann, 1982;Changeux et al, 1984;Boyd, 1987]. Importantly for the above model, Feltz and Trautmann (1982) reported that the two kinetically distinguishable components of desensitization do not behave independently-the relative amplitude of the fast phase of onset is not necessarily reflected by an equal contribution to recovery (but see Maconochie and Knight, 1992).…”

“…Interestingly, these two values are quite similar to the two affinities estimated from [ 3 H]nicotine binding to high affinity sites in brain (Lippiello et al, 1987;see below). The activatable, low affinity resting state R has a dissociation constant for ACh of about 50 -100 M (Changeux et al, 1984; see also e.g., Colquhoun and Ogden, 1988). Assuming diffusion-limited agonist binding (10 8 -10 9 M Ϫ1 s Ϫ1 ), the estimated rate of ACh dissociation from the D state would be Ϸ1 s Ϫ1 .…”