Ginsenosides act as positive modulators of P2X4 receptors

Dhuna, Kshitija, Felgate, Matthew, Bidula, Stefan, Walpole, Samuel, Bibic, Lucka, Cromer, Brett, Angulo, Jesus, Sanderson, Julie, Stebbing, Martin and Stokes, Leanne (2019) Ginsenosides act as positive modulators of P2X4 receptors. Molecular Pharmacology, 95 (2). pp. 210-221. ISSN 0026-895X

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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 2 or ATP 1 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.

Item Type: Article
Uncontrolled Keywords: atp receptors,p2x receptors,nucleotides,docking proteins,crispr,drug discovery,pharmacology ,/dk/atira/pure/subjectarea/asjc/3000/3004
Faculty \ School: Faculty of Science > School of Pharmacy
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Depositing User: LivePure Connector
Date Deposited: 20 Dec 2018 16:31
Last Modified: 24 May 2022 13:10
DOI: 10.1124/mol.118.113696

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