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Drosophila taste neurons as an agonist-screening platform for P2X receptors

Grimes, Leanne, Griffiths, Julia, Pasqualetto, Gaia, Brancale, Andrea ORCID:, Kemp, Paul J. ORCID:, Young, Mark T. ORCID: and van der Goes van Naters, Wynand ORCID: 2020. Drosophila taste neurons as an agonist-screening platform for P2X receptors. Scientific Reports 10 , 8292. 10.1038/s41598-020-65169-9

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The P2X receptor family of ATP-gated cation channels are attractive drug targets for pain and inflammatory disease, but no subtype-selective agonists, and few partially selective agonists have been described to date. As proof-of-concept for the discovery of novel P2X receptor agonists, here we demonstrate the use of Drosophila taste neurons heterologously expressing rat P2X2 receptors as a screening platform. We demonstrate that wild-type rat P2X2 expressed in Drosophila is fully functional (ATP EC50 8.7 µM), and that screening of small (2 µl) volumes of a library of 80 adenosine nucleotide analogues is rapid and straightforward. We have determined agonist potency and specificity profiles for rat P2X2 receptors; triphosphate-bearing analogues display broad activity, tolerating a number of substitutions, and diphosphate and monophosphate analogues display very little activity. While several ATP analogues gave responses of similar magnitude to ATP, including the previously identified agonists ATPγS and ATPαS, we were also able to identify a novel agonist, the synthetic analogue 2-fluoro-ATP, and to confirm its agonist activity on rat P2X2 receptors expressed in human cells. These data validate our Drosophila platform as a useful tool for the analysis of agonist structure-activity relationships, and for the screening and discovery of novel P2X receptor agonists.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: Nature Publishing Group
ISSN: 2045-2322
Funders: BBSRC, MRC
Date of First Compliant Deposit: 1 June 2020
Date of Acceptance: 28 April 2020
Last Modified: 05 Jan 2024 05:48

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