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.