Taspine is a natural product that suppresses P2X4 receptor activity via phosphoinositide 3‐kinase inhibition

Nadzirin, Izzuddin Bin, Fortuny‐Gomez, Anna, Ngum, Neville, Richards, David, Ali, Seema, Searcey, Mark ORCID: https://orcid.org/0000-0003-2273-8949 and Fountain, Samuel J. ORCID: https://orcid.org/0000-0002-6028-0548 (2021) Taspine is a natural product that suppresses P2X4 receptor activity via phosphoinositide 3‐kinase inhibition. British Journal of Pharmacology, 178 (24). pp. 4859-4872. ISSN 0007-1188

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Background and Purpose: P2X4 is a ligand-gated cation channel activated by extracellular ATP involved in neuropathic pain, inflammation and arterial tone. Experimental Approach: Natural products were screened against human or mouse P2X4 activity using fura-2 loaded 1321N1 cells for measurement of intracellular Ca 2+ responses. Whole-cell currents were measured by patch clamp. Human primary macrophage chemokine release was used to assess effect of taspine on inflammatory cell function. An enzymatic assay was performed to assess the effect of taspine on recombinant PI3-kinase. Key Results: A natural product screen identified taspine as an inhibitor of human P2X4 activity. Taspine inhibits human and mouse P2X4-mediated Ca 2+ influx in 1321N1 cells expressing receptors but lacked activity at human P2X2, P2X3, P2X2/3 and P2X7 receptors. Taspine inhibited the maximal response at human and mouse P2X4 but effective on ATP potency. Taspine has a slow onset rate (~15 min for half-maximal inhibition), irreversible over 30 min of washout. Taspine inhibits P2X4-mediated Ca 2+ signalling in mouse BV-2 microglia cells and human primary macrophage. Taspine inhibited P2X4-mediated CXCL5 secretion in human primary macrophage. Taspine reversed ivermectin-induced potentiation of P2X4 currents in 1321N1 stably expressing cells. The PI3-kinase inhibitor LY294002 mimicked the properties of taspine on P2X4-mediated Ca 2+ influx and whole-cell currents. Taspine directly inhibited the enzymatic activity of recombinant PI3-kinase in a competitive manner. Conclusion and Implications: Taspine is a novel natural product P2X4 receptor inhibitor, mediating its effect through PI3-kinase inhibition rather than receptor antagonism. Taspine can inhibit the pro-inflammatory signalling by P2X4 in human primary macrophage.

Item Type: Article
Additional Information: Funding Information: This work was funded by a British Heart Foundation grant (PG/16/69/32194) awarded to S.J.F. and Malaysian Government Studentship awarded to I.B.N.
Uncontrolled Keywords: p2x receptor,ion channel,natural product,purinergic,pharmacology ,/dk/atira/pure/subjectarea/asjc/3000/3004
Faculty \ School: Faculty of Science > School of Biological Sciences
Faculty of Science > School of Pharmacy
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Depositing User: LivePure Connector
Date Deposited: 19 Aug 2021 00:30
Last Modified: 23 Oct 2022 02:55
URI: https://ueaeprints.uea.ac.uk/id/eprint/81150
DOI: 10.1111/bph.15663


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