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Description
Drug addiction and neurological disorders have long been linked to nicotinic acetylcholine receptors (nAChRs). The nAChRs are implicated in diseases including schizophrenia, drug addiction (specifically nicotine addiction), Alzheimer’s, and Parkinson’s diseases. They are composed of an extracellular domain (ECD), which contains the ligand binding site, a transmembrane domain which contains the ion-channel gate and forms the pore, and an intracellular domain (ICD) which is generally thought to play a role in receptor regulation and trafficking. Very little is currently understood about the unresolved ICD. Among the 16 nAChR subunits that yield a vast array of stoichiometric subtypes, the mammalian neuronal nAChRs contain two predominant compositions: the homomeric α7-nAChR and the heteromeric α4β2*-nAChR, where * denotes the possibility of an additional accessory subunit. Although the general pentameric arrangement is α-β-α-β-α/β, a vast stoichiometric variability exists and leads to unique localization, for which the mechanism remains unclear, of the specific nAChR subtype variants. For α4β2*-nAChRs, a distinction in the localization between (α4)3(β2)2, (α4)2(β2)3, and (α4)2(β2)2* subtypes is not possible using current biochemical techniques. Unfortunately, many years of pharmacological study also have not yielded robust therapies for the maledictions caused by a dysfunction of nAChRs. There is still a profound lack of information about the ICD and the regulation/trafficking of these receptors. Targeting their regulatory proteins may combat neurodegenerative disorders better than targeting the receptors themselves. Therefore this proposal aims to study and elucidate the mechanisms of regulation of nAChRs.