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Title: Pharmacological characterisation of neuronal nicotinic acetylcholine receptors
Author: Chatzidaki, A.
ISNI:       0000 0004 5369 283X
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2015
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Nicotinic acetylcholine receptors (nAChRs) are the targets for the endogenous neurotransmitter acetylcholine and represent a diverse family of ligand-gated ion channels. They are expressed in the neuromuscular junction, the peripheral nervous system and the central nervous system. In the brain, the most prevalent subtypes are the heteromeric α4β2 and homomeric α7 nAChRs. Neuronal nAChRs are implicated in numerous physiological and pathophysiological functions and are therefore important targets for therapeutic drug discovery for conditions such as Alzheimer’s disease, schizophrenia and tobacco addiction. This thesis aims to further our understanding of the pharmacological and molecular characteristics of neuronal nAChRs. Acetylcholine activates nAChRs by binding at an extracellular orthosteric site. Previous studies have described several ligands that potentiate agonist-evoked responses by binding to an allosteric site of the α7 nAChRs that is distinct from the acetylcholine binding site. These ligands, termed positive allosteric modulators (PAMs) can be described as type I, when they have little or no effect on desensitisation, or type II, when they dramatically slow down the fast desensitisation kinetics of the α7 nAChR subtype. Here, a novel series of α7-selective PAMs with a range of effects on receptor desensitisation is described, using recombinant human receptors. This series consists of PAMs with type I and type II profiles, in addition to PAMs with intermediate properties on desensitisation, therefore increasing the nAChR pharmacological toolbox. Furthermore, the effect of a number of mutations on the pharmacological properties of the receptor is investigated. Three point mutations, two in the transmembrane domain (L247T and M260L) and one in the N-terminal domain (W54A), are shown to have the ability to convert PAMs into agonists. Moreover, the M260L mutation displays this property only with PAMs that have a significant effect on receptor desensitisation. These observations can provide insights into the role of these residues on receptor gating and desensitisation. In addition to the studies on recombinant receptors, the expression and functional properties of nAChRs in neurons derived from human induced pluripotent stem cells (iPSC) is examined. The iPSC-derived neurons represent a potentially valuable tool for the characterisation of neuronal receptors and ion channels in a native environment.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available