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Title: Molecular and functional characterisation of nicotinic acetylcholine receptor chimaeras
Author: Kracun, Sebastian
ISNI:       0000 0004 2673 4010
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2008
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Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels which exhibit considerable subunit diversity. They have been implicated in processes including synaptic transmission and modulation of neurotransmitter release. They also have a significant role in several pathological disorders as well as nicotine addiction, which makes nAChRs important targets for therapeutic drug discovery. One of the aims of this study was to investigate the influence of the intracellular domain of nAChR subunits upon receptor assembly, targeting and functional properties. A series of subunit chimaeras was constructed, each containing the intracellular loop region, located between transmembrane (TM) domains M3 and M4, from nAChR subunits al-alO or pl-p4 and from the 5-hydroxytryptamine type 3 receptor (5-HT3R) subunits 3 A and 3B. Evidence has been obtained which demonstrates that the large intracellular loop exerts a significant influence upon the levels of both cell-surface and intracellular assembled receptors. Comparisons of functional ion-channel properties revealed a significant influence upon both single-channel conductance and receptor desensitisation. Experiments conducted in polarised epithelial cells demonstrate that the nAChR loop can also influence receptor targeting. In a further study, the influence of the recently identified nAChR molecular chaperone, RIC-3 (resistance to mhibitors of cholinesterase), on receptor maturation was investigated. The influence of subunit domains upon the RIC-3's chaperone activity was investigated by co-expression with subunit chimaeras. Finally, a9/5-HT3A and alO/5-HT3A subunit chimeras were used to investigate the pharmacological properties of a9al0 nAChRs, a receptor subtype expressed in hair cells of the auditory system. Physiologically relevant concentrations of the anti-malarial compounds, quinine, quinidine and chloroquine were shown to act as competitive inhibitors, whereas the NMDA receptor antagonist, neramexane, blocked a9al0 nAChR mediated responses via a non-competitive mechanism.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available