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    Structural and functional studies of cannabidiol interactions with voltage-gated sodium channels

    Goodyer Sait, Lily Jane (2022) Structural and functional studies of cannabidiol interactions with voltage-gated sodium channels. PhD thesis, Birkbeck, University of London.

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    Abstract

    Cannabidiol (CBD), is a major non-psychoactive compound isolated from the cannabis plant and has been associated with the treatment of a range of conditions which are often related to voltage-gated sodium ion channels (VGSCs). The aim of this research was to use X-ray crystallography to provide a detailed insight into the interactions which occur between CBD and the prokaryotic VGSC NavMs. CBD was found to bind at a novel site deep within the fenestration of NavMs, near the central hydrophobic cavity (Sait et al., 2020). Binding at this site would block sodium ion translocation, thus providing a mechanistic explanation for CBD’s channel inhibitory effects, which were validated via electrophysiology experiments performed on designed mutants in collaborative studies with the Ruben lab (Simon Fraser University).In addition, modelling studies conducted suggested why the closely related psychoactive compound tetrahydrocannabinol (THC) may have different binding interactions with VGSCs. Comparisons were also made between the proposed Transient Receptor Potential Cation Subfamily V member 2 (TRPV2) channel CBD binding site and the NavMs binding site. Finally, thermal melt circular dichroism spectroscopic experiments were carried out to explore CBD interactions with NavMs, which showed CBD does not affect NavMs stability during interaction. In summary, this study provides, for the first time, an insight into the possible mechanism underlying CBD interactions with sodium channels.

    Metadata

    Item Type: Thesis
    Copyright Holders: The copyright of this thesis rests with the author, who asserts his/her right to be known as such according to the Copyright Designs and Patents Act 1988. No dealing with the thesis contrary to the copyright or moral rights of the author is permitted.
    Depositing User: Acquisitions And Metadata
    Date Deposited: 14 Jun 2022 14:46
    Last Modified: 01 Nov 2023 15:36
    URI: https://eprints.bbk.ac.uk/id/eprint/48458
    DOI: https://doi.org/10.18743/PUB.00048458

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