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    Ginsenosides Act As Positive Modulators of P2X4 Receptors

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    Author
    Dhuna, K; Felgate, M; Bidula, SM; Walpole, S; Bibic, L; Cromer, BA; Angulo, J; Sanderson, J; Stebbing, MJ; Stokes, L
    Date
    2019-02-01
    Source Title
    Molecular Pharmacology
    Publisher
    AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
    University of Melbourne Author/s
    Stebbing, Martin
    Affiliation
    Anatomy and Neuroscience
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Dhuna, K., Felgate, M., Bidula, S. M., Walpole, S., Bibic, L., Cromer, B. A., Angulo, J., Sanderson, J., Stebbing, M. J. & Stokes, L. (2019). Ginsenosides Act As Positive Modulators of P2X4 Receptors. MOLECULAR PHARMACOLOGY, 95 (2), pp.210-221. https://doi.org/10.1124/mol.118.113696.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/253628
    DOI
    10.1124/mol.118.113696
    Abstract
    We investigated the selectivity of protopanaxadiol ginsenosides from Panax ginseng acting as positive allosteric modulators on P2X receptors. ATP-induced responses were measured in stable cell lines overexpressing human P2X4 using a YOPRO-1 dye uptake assay, intracellular calcium measurements, and whole-cell patch-clamp recordings. Ginsenosides CK and Rd were demonstrated to enhance ATP responses at P2X4 by ∼twofold, similar to potentiation by the known positive modulator ivermectin. Investigations into the role of P2X4 in mediating a cytotoxic effect showed that only P2X7 expression in HEK-293 cells induces cell death in response to high concentrations of ATP, and that ginsenosides can enhance this process. Generation of a P2X7-deficient clone of BV-2 microglial cells using CRISPR/Cas9 gene editing enabled an investigation of endogenous P2X4 in a microglial cell line. Compared with parental BV-2 cells, P2X7-deficient BV-2 cells showed minor potentiation of ATP responses by ginsenosides, and insensitivity to ATP- or ATP+ ginsenoside-induced cell death, indicating a primary role for P2X7 receptors in both of these effects. Computational docking to a homology model of human P2X4, based on the open state of zfP2X4, yielded evidence of a putative ginsenoside binding site in P2X4 in the central vestibule region of the large ectodomain.

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