Collins, T.; (2010) Molecular pharmacological characterisation of neuronal nicotinic acetylcholine receptors. Doctoral thesis , UCL (University College London).

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) are excitatory ligand‐gated ion channels that perform important roles throughout the nervous systems of both vertebrate and invertebrate organisms. Impairments to human nAChRs and cholinergic transmission are thought to underlie the pathophysiologies of several neurological and psychological diseases including schizophrenia, Alzheimer’s disease, Parkinson’s disease and certain forms of epilepsy. They are also the receptors that mediate the effects of tobacco smoking and contribute to the physiological and psychological changes associated with nicotine addiction. The aim of this thesis is to further our understanding of neuronal nAChRs from a pharmacological and molecular viewpoint. Research described in this thesis focuses on numerous aspects of neuronal nAChRs; allosteric modulators, insect nAChRs and chaperone proteins. Allosteric modulators of nAChRs are ligands that alter the receptor’s responsiveness to agonists via sites that are separate from the agonist‐binding site (the orthosteric site). Positive allosteric modulators (PAMs) increase the receptor's sensitivity to agonist acetylcholine whereas negative allosteric modulators (NAMs) decrease sensitivity. Using molecular and electrophysiological techniques on the α7 nAChR, studies have been conducted with three PAMs (ivermectin, NS‐1738 and PNU‐120596) and one NAM (methanandamide). Chimeric receptor constructs and site‐directed mutagenesis studies, together with ligand docking simulations, have highlighted the importance of the transmembrane region of the α7 nAChR for modulation by these ligands. The second topic covered by this thesis is insect nAChRs and the molecular chaperone RIC‐3 (resistance to cholinesterase inhibitors); a protein that facilitates folding and assembly of nAChRs. In the past, recombinant expression of insect receptors has proved largely unsuccessful and in some (but not all) circumstances co‐expression with RIC‐3 has alleviated the problems. This research is aimed at investigating the influence of alternatively spliced isoforms of Drosophila melanogaster RIC‐3 on the maturation of a variety Drosophila recombinant nAChR subunits. Lastly, ongoing work is also described on the cloning of insect nAChR subunits from pest species Frankliniella occidentalis (western flower thrip), which has developed resistance to the insecticide spinosad.

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