Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604706
Title: Modulation of the heat- and capsaicin-gated channel TRPV1 : role of NGF and PKC beta
Author: Huang, J.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2006
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Abstract:
Nerve growth factor (NGF), one of the major inflammatory mediators released following tissue injury, causes thermal hyperalgesia by sensitisation of the heat- and capsaicin-gated ion channel, TRPV1. The molecular mechanisms by which NGF causes sensitisation of TRPV1 remain controversial. In this thesis, the functional effect of NGF on TRPV1 was investigated in HEK 293 cells and cultured mouse dorsal root ganglion (DRG) neurons using calcium imaging. The results support the hypothesis that sensitisation of TRPV1 by NGF is mediated by two pathways. The major pathway is activated by the Y760 site TrkA, which stimulates P13 kinase with Src kinase being involved at a subsequent stage. Src kinase phosphorylates TRPV1 at a single tyrosine residue, Y200, leading to trafficking and insertion of the channel into the surface membrane and thus enhancing the membrane ionic currents. The second and more minor pathway is the PLCγ / PKCε signalling pathway which causes phosphorylation TRPV1 at the S502 and S801 sites. The actions of different PKC isoforms in modulating TRPV1 are largely unknown. PKCβ was found to be located in the membrane of small DRG neurones from wild-type mice but in the cytoplasm of neurones from TRPV1 knockout mice, suggesting a physical interaction between PKCβ and TRPV1. Immunoprecipitation and in vitro GST pull down experiments confirmed that PKCβ binds predominantly to the N-terminal of TRPV1. The protein-protein interaction between PKCβ and TRPV1 suggests that PKCβ might play a specific role in modulation of TRPV1. These findings provide new insights into the molecular mechanisms underlying TRPV1 modulation by inflammatory mediators and PKC isoforms.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.604706  DOI: Not available
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