CHAPTER 15: Allosteric Modulation of Neuronal Nicotinic Acetylcholine Receptors Check Access

Nicotinic acetylcholine receptors (nAChRs) are a diverse family of integral membrane proteins involved in neurotransmission. These pentameric complexes, of numerous subtypes, are expressed in nervous tissue, striated muscle and some non-neuronal tissues. The nAChRs are quintessential allosteric proteins in that they function to change conformation, from closed to open, upon activation with the endogenous ligand acetylcholine. This opening allows ions to pass across the cell membrane, thus transforming a chemical signal into an electrical one. Neuronal nAChRs mediate many neurophysiological and cognitive processes; as such, they are implicated in important disease states such as schizophrenia, Alzheimer's and Parkinson's diseases, as well as being the molecular point of origin for addiction to nicotine. Although allosteric modulation of nicotinic receptors is recognized as important, our currently limited understanding of molecular mechanisms of this modulation undermines development of clinical applications. In this chapter, we sketch a conceptual framework for allosteric modulation of nAChRs that embraces the inherent symmetry of the system and that treats agonist activation and positive and negative modulation as a functional spectrum.