Willoughby, John Julian; (1994) Ligand-Gated Ion Channels in Sensory Neurons. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

A subset of sensory neurons whose cells bodies lie within the dorsal root ganglia (DRG) are nociceptive - their activation in response to noxious stimuli can lead to the sensation of pain. The focus of this work was to try to clone ligand-gated ion channels (LGICs) that might be involved in the activation of these neurons, in particular, the capsaicin receptor which is expressed only in nociceptive neurons. Firstly, a human cDNA library made from material containing sensory ganglia was screened by low stringency homology hybridisation using LGIC cDNA probes containing conserved transmembrane domains. This approach was devised to identify novel LGICs, including the capsaicin receptor. The strategy resulted in the cloning of the novel human homologue of the nicotinic acetylcholine receptor (nAChR) 3 subunit. Secondly, a rat DRG cDNA expression library was screened for fusion proteins that would bind to resiniferatoxin (RTX), a toxin which binds to the capsaicin receptor. Several RTX-binding proteins were isolated, but none exhibited properties that suggested they were components of the capsaicin receptor. NGF levels are raised following tissue injury and increases in NGF levels can cause hyperalgesia. The effect of NGF on mRNA levels of nAChR subunits in cultures of rat DRG neurons was investigated to see if NGF increased nAChRs, contributing to hyperalgesia. The complement of nAChR subunits in these cells was determined, and NGF was shown to have no effect on levels of mRNA of nAChR subunits. The intracellular signalling pathways by which NGF induces hyperglesia are unknown. Transcription factors can be a downstream target of tyrosine receptor activation. The effects of NGF on the expression of the neuronal transcription factors Brn-3 and Oct-2 in DRG cultures was examined. NGF was shown to have no effect on Brn-3, however, Oct-2 levels increased four-fold, a change reflected in Oct-2 protein levels.

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