Ginsenosides Act As Positive Modulators of P2X4 Receptors
AuthorDhuna, K; Felgate, M; Bidula, SM; Walpole, S; Bibic, L; Cromer, BA; Angulo, J; Sanderson, J; Stebbing, MJ; Stokes, L
Source TitleMolecular Pharmacology
PublisherAMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
University of Melbourne Author/sStebbing, Martin
AffiliationAnatomy and Neuroscience
Document TypeJournal Article
CitationsDhuna, 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 StatusOpen Access
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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