ALLOSTERIC NICOTINIC RECEPTORS, HUMAN PATHOLOGIES

Nicotinic acetylcholine receptors are ligand-gated ion channels presen t in muscle and brain. These allosteric oligomers may exist in several conformational states which include a resting state, an open-channel state, and a desensitized refractory state. Recent work has shown that point mutations in the nicotinic receptor may, altogether, abolish de sensitization, increase apparent affinity for agonists and convert the effect of a competitive antagonist into an agonist response. These pl eiotropic effects are interpreted in terms of the allosteric model. Th is paper reviews recent evidence that such mutations occur spontaneous ly in humans and may cause diseases such as congenital myasthenia or f amilial frontal lobe epilepsy. In addition, nicotinic receptors are in volved in tobacco smoking. Accumulating evidence, including experiment s with knock-out animals, indicates that addiction to nicotine is link ed to the activation of beta 2-subunit containing nicotinic receptors in the dopaminergic mesolimbic neurons which are part of the reward sy stems in the brain. Current research also indicates that nicotinic ago nists might serve as therapeutic agents for Alzheimer's disease and To urette's syndrome, as well as for schizophrenia. This paper extends an d updates a recently published review. ((C) Elsevier, Paris).