Introductory Lecture: Allosteric Modulation of Torpedo Nicotinic Acetylcholine Receptor Ion Channel Activity by Noncompetitive Agonists

Abstract

Similar to other neuroreceptors of the vertebrate central nervous system, the nicotinic acetylcholine receptor (nAChR) is subject to modulatory control by allosterically acting ligands. Of particular interest in this regard are allosteric ligands that enhance the sensitivity of the receptor to its natural agonist acetylcholine (ACh), as such ligands could be useful as drugs in diseases associated with impaired nicotinic neurotransmission. Here we discuss the action of a novel class of nAChR ligands which act as allosterically potentiating ligands (APL) on the nicotinic responses induced by ACh and competitive agonists. In addition, APLs also act as noncompetitive agonists of very low efficacy, and as direct blockers of ACh-activated channels. These actions are observed with nAChRs from brain, muscle and electric tissue, and they depend on the structure of the APL and the concentration range applied. We focus here on Torpedo nAChR because (i) the unusual pharmacology of these ligands was first discovered with this system, and (ii) large quantities of this receptor are readily available for biochemical studies.

A Novel Class of Peptides with Facilitating Action on Neuronal Nicotinic Receptors of Rat Chromaffin Cells in Vitro: Functional and Molecular Dynamics Studies

“…When used at submicromolar concentration APLs facilitate nicotine-induced responses even if generated by desensitized receptors, whereas a 10 times higher dose depresses nAChR-mediated responses (Maelicke et al, 1997;Maelicke and Albuquerque, 2000). This property was confirmed in the present study with physostigmine, which enhanced nicotine currents at 0.5 M and depressed them at 5 M concentration.…”

“…APLs often produce a biphasic action such that, in low doses, they facilitate agonist responses, whereas in higher doses they depress them. One example of an APL is physostigmine that at the concentration of 0.5 M maximally enhances nAChRs via allosteric modulation, whereas at higher concentrations, it actually inhibits them (Maelicke et al, 1997). In the present investigation, we first tested whether this action of physostigmine was also present on native nAChRs of chromaffin cells.…”

“…These drugs bind to a discrete site of nAChRs from which they allosterically up-or down-regulate the action of nicotinic agonists (Maelicke et al, 1997;Changeux and Edelstein, 1998;Maelicke and Albuquerque, 2000). APLs often produce a biphasic action such that, in low doses, they facilitate agonist responses, whereas in higher doses they depress them.…”

“…Hence, the identification of chemicals that can selectively potentiate responses mediated by nAChRs is clearly a major goal to develop potential therapeutic drugs. So far, two main classes of compounds have been used for this purpose: cholinesterase inhibitors, which prevent breakdown of endogenous ACh and thus lead to a build up of this transmitter at the receptor level (Maelicke and Albuquerque, 2000), and allosterically potentiating ligands (APLs) of nAChRs, which enhance ACh interaction with its receptors (Maelicke et al, 1997;Krause et al, 1998). Although these substances have been shown to induce clinical benefit (Maltby et al, 1994;Nordberg et al, 1998;Sjoberg et al, 1998), either approach has some pitfalls.…”

Galantamine-induced Amyloid-β Clearance Mediated via Stimulation of Microglial Nicotinic Acetylcholine Receptors

“…Several lines of evidence suggest that the therapeutic effects of galantamine are mediated by additional mechanisms apart from AChE inhibition. Galantamine actually acts as an allosterically potentiating ligand (APL) for nicotinic acetylcholine receptors (nAChRs) (17)(18)(19)(20) and exhibits neuroprotective effects in vitro (21) and in vivo (22).…”