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Title: Characterisation of the sialogogic properties of transient receptor potential channel agonists
Author: Houghton, Jack William
ISNI:       0000 0004 7970 0164
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
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Chemesthetic transient receptor potential (TRP) channels are expressed in the oral cavity by free afferent nerve endings in the epithelium of oral tissues. The TRPV1 agonists; capsaicin, nonivamide and piperine have been shown to increase salivary flow when introduced to the oral cavity but the sialogogic properties of other TRP channel agonists have not been investigated nor has their mechanism of action. Nonivamide and menthol, a TRPM8 agonist, provoked greater whole mouth saliva (WMS) and labial gland flow rates, and WMS protein output than unstimulated saliva. In addition, the vehicle control, propylene glycol (PG), was also found to have sialogogic properties. Furthermore, nonivamide was found to increase the abundance of cystatin S in secreted saliva. The effect that TRP channel agonists have on low abundance salivary proteins, the proteome as a whole, and the function of the proteome was investigated using a multi-batch quantitative mass spectrometry method novel to salivary proteomics. Inter-personal but also inter-mouth rinse variation was observed in the secreted proteomes and, using a novel method of proteomic data analysis, inter-day variation was identified after some of the mouth rinses. Furthermore, significant changes in specific proteins were identified in the WMS after all mouth rinses and these changes were attributed to functional shifts in the WMS secreted in response to nonivamide, primarily the over representation of salivary and non-salivary cystatins. The observations from the first two studies, specifically increased flow rates of labial minor glands in response to nonivamide and menthol rinsing, and that the increased abundance of salivary cystatins not being associated with increases in other non-parotid associated proteins, led to the hypothesis that there are direct interactions between TRP channel agonists and minor salivary glands. The TRP channel expression of a salivary acinar cell model, SMG C6 cells, was characterised along with intracellular calcium [Ca2+]i responses to nonivamide, menthol and cinnamaldehyde, a TRPA1 agonist. Surprisingly, it was found that whilst TRPA1 and TRPM8 are not expressed by SMG C6 cells, both cinnamaldehyde and menthol induced a SMG C6 [Ca2+]i response. Further investigation found that this response is not mediated by TRP channels. Conversely, TRPV1 is expressed by SMG C6 cells but the cells do not have a [Ca2+]i response to nonivamide. Overall, the work presented in this thesis characterises the sialogogic properties of the TRP channel agonists nonivamide, menthol and cinnamaldehyde, including altered fluid secretion and protein composition. This study puts forward a theory of how TRP channel agonists might act through an autonomic nerve mediated reflex alongside direct action on minor glands.
Supervisor: Proctor, Gordon Burgess ; Carpenter, Guy Howard Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available