Cholinergic drugs potentiate human nicotinic α4β2 acetylcholine receptors by a competitive mechanism

Abstract

Effects of cholinergic drugs on human a4h2 nicotinic acetylcholine receptors expressed in Xenopus oocytes have been investigated in electrophysiological and ligand binding experiments. Atropine, scopolamine, physostigmine, and tacrine combine potentiation of ion current induced by low concentrations of acetylcholine with inhibition of ion current evoked by high concentrations of acetylcholine. Rivastigmine, galanthamine, and dichlorvos cause only inhibition of ion current evoked by low concentrations of acetylcholine. Binding experiments show that the potentiating cholinergic drugs atropine, scopolamine, and physostigmine are competitive ligands of human a4h2 nicotinic acetylcholine receptors. Conversely, the inhibitory cholinergic drugs galanthamine and rivastigmine are non-competitive. The noncompetitive drugs are not allosteric, since they do not affect the saturation curve of the radioligand [ 3 H]cytisine. Effects of potentiating cholinergic drugs on nicotinic acetylcholine receptors are consistent with and predicted by a model comprising competitive drug effects at two equivalent agonist recognition sites on the nicotinic acetylcholine receptor combined with non-competitive ion channel block. D

Functional Characterization of AT-1001, an α3β4 Nicotinic Acetylcholine Receptor Ligand, at Human α3β4 and α4β2 nAChR

“…22 This equation was subsequently elaborated further to take into account the possibility that the test compound might also act as an open-channel blocker. 23 The present data also allow further insight into the functional selectivity of AT-1001 for the human α3β4 nAChR versus the human α4β2 nAChR. AT-1001 binds with about 100-fold higher affinity to rat α3β4 and human α3β4α5 nAChR than to rat α4β2 nAChRs.…”

“…Similar effects were previously reported for cholinergic drugs at α4β2 nAChRs. 23,26 The AT-1001 concentration-inhibition curve at α3β4 nAChR ( Figure 3B) therefore has a complex shape that is better fitted by a two-site equation (Equation 1) that was initially developed to take into account the bell-shaped inhibition curve observed with some antagonists at the α3β4 nAChR. 22 This equation was subsequently elaborated further to take into account the possibility that the test compound might also act as an open-channel blocker.…”

Potentiating and blocking actions of neonicotinoids on the response to acetylcholine of the neuronal .ALPHA.4.BETA.2 nicotinic acetylcholine receptor

“…Similar actions have also been observed for d-tubocurarine, 17) atropine 18) and choline, 19) and these observations have been interpreted in terms of an equilibrium two-site receptor occupation model. 19,20) According to this model, sequential occupation of the two agonist binding sites by two different agonists greatly enhances the probability of opening the nAChR channel. Potentiation by imidacloprid and clothianidin of the ACh-induced response may also be accounted for in a similar fashion, because the action was reduced by increasing the ACh concentration (Figs.…”

Amyloid β Protein Modulates Glutamate-Mediated Neurotransmission in the Rat Basal Forebrain: Involvement of Presynaptic Neuronal Nicotinic Acetylcholine and Metabotropic Glutamate Receptors

“…Second, the nAChR system could serve as a potential avenue for the treatment of AD. In fact, of the current crop of acetylcholinesterase inhibitors routinely used in the treatment of mild to moderate AD, one agent (galantamine) has been identified to have activity at the nicotinic receptors in the brain (Smulders et al, 2005). Finally, because the depressant effects of A␤ 1-42 on cholinergic cells are expressed through presynaptic mGluRs, the latter receptors may represent novel therapeutic targets for AD therapies.…”