Allosteric Receptors: From Electric Organ to Cognition

Abstract

This autobiography covers the past 50 years beginning with the development of the concept of allosteric proteins and its application to pharmacological receptors. It continues with the identification of the nicotinic acetylcholine receptor, the discovery of its molecular organization, the structure of the acetylcholine-binding site and of the ion channel, and the demonstration of its allosteric transitions. The article then traces the origins of the concept of allosteric modulator and its consequences in pharmacology. It proceeds with the theory of selective stabilization of synapses and with experimental studies carried out on the contribution of the nicotinic receptor in the morphogenesis of the neuromuscular junction. The knowledge acquired with the nicotinic receptor is further exploited to reach higher levels of brain organization, and the contribution of nicotinic receptors to the action of nicotine on reward and cognition is explored, in particular, using a novel experimental strategy that combines nicotinic receptor genes knock-out and stereotaxic gene re-expression. Theoretical models of cognitive functions are proposed that link the molecular to the cognitive level. The report ends with a discussion on nicotinic receptors and the pharmacology of the future.

Subunit stoichiometry and arrangement in a heteromeric glutamate-gated chloride channel

“…Hence, an alternative methodology must be considered. In Cys-loop receptors, the neurotransmitter-binding pockets lie at the interface between adjacent subunits (1)(2)(3)(4)(5)(6)(7)(8)(9). One could therefore use site-specific mutagenesis and biophysical characterization of activation mechanisms in recombinant receptors to find the types of subunits that line the agonist-binding pockets.…”

“…They belong to the Cys-loop receptor superfamily of transmembrane oligomers that open an intrinsic cationic or anionic channel pore upon binding of neurotransmitters, such as ACh, serotonin, GABA, Gly, histamine, or Glu (1)(2)(3)(4)(5)(6)(7)(8)(9). GluClRs are specific targets for ivermectin (IVM), a broad-spectrum anthelmintic drug used to treat filarial diseases like onchocerciasis (river blindness) and elephantiasis (lymphatic filariasis) that afflict hundreds of millions of people worldwide (10,11).…”

α6β2* and α4β2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease

“…Although this review is focused on nAChRs within the basal ganglia, it is important to emphasize that nAChR subtypes occur throughout the central and peripheral nervous systems, as well as on some non-neuronal cells. Thus nAChRs influence many physiological mechanisms, including pain, inflammation, cognition, and others (Bacher et al, 2009;Buckingham et al, 2009;McIntosh et al, 2009;Poorthuis et al, 2009;Sarter et al, 2009;Changeux, 2010a;Mineur and Picciotto, 2010;Philip et al, 2010). As a consequence, systemic nicotine and other agonists have many and varied biological effects, beyond the modulation of motor control.…”

Ciblage thérapeutique des récepteurs couplés aux protéines G

“…Ceci le distingue du principe actif orthostérique qui interfère de façon indifférenciée avec le récepteur, Né dans les années 1960, le concept d'interaction allostérique décrit des interactions protéiques associant des sites d'interaction différents [1]. Ce concept fondateur, qui englobe une multitude de mécanismes moléculaires du vivant, trouve en particulier des applications dans le domaine pharmacologique avec le développement de principes actifs interagissant avec différentes familles de récepteurs membranaires [2]. Environ 30 % des médicaments sur le marché agissent sur des récepteurs couplés aux protéines G (RCPG), cette famille de gènes étant donc la plus ciblée [3].…”