Minard, A, Bauer, CC, Chuntharpursat-Bon, E et al. (8 more authors) (2019) Potent, selective, and subunit‐dependent activation of TRPC5 channels by a xanthine derivative. British Journal of Pharmacology, 176 (20). pp. 3924-3938. ISSN 0007-1188
Abstract
Background and purpose
TRPC1, TRPC4 and TRPC5 can form homo‐ or heterotetrameric, calcium‐permeable cation channels that have been implicated in various disease states. Recent research has yielded specific and potent xanthine‐based TRPC1/4/5 inhibitors. Here we investigated the possibility of xanthine‐based activation.
Experimental approach
An analogue of the TRPC1/4/5 inhibitor Pico145, AM237, was synthesised and its activity was investigated using HEK cells over‐expressing TRPC4, TRPC5, TRPC4–C1, TRPC5–C1, TRPC1:C4 or TRPC1:C5, and in A498 cells expressing native TRPC1:C4 channels. TRPC1/4/5 ion channel activities were measured by [Ca²⁺]i measurements and by patch‐clamp electrophysiology. Selectivity of AM237 was tested against TRPC3, TRPC6, TRPV4 or TRPM2.
Key results
AM237 potently activated TRPC5:C5 channels in [Ca²⁺]i measurements (EC₅₀ 15‐20 nM), and potentiated TRPC5:C5 activation by sphingosine‐1‐phosphate, yet suppressed TRPC5:C5 channel activity evoked by (‐)‐englerin A (EA). In patch‐clamp studies AM237 also activated TRPC5:C5 channels, with greater effect at positive voltages, but it was a weaker activator than EA. Pico145 competitively inhibited AM237‐induced TRPC5:C5 activation. In contrast, AM237 did not activate TRPC4:C4, TRPC4–C1, TRPC5–C1, TRPC1:C5 and TRPC1:C4 channels, nor native TRPC1:C4 channels in A498 cells, but potently inhibited EA‐dependent activation of these channels with IC50 values ranging from 0.9 to 7 nM. AM237 (300 nM) did not activate or inhibit TRPC3, TRPC6, TRPV4 or TRPM2 channels.
Conclusions and implications
This study suggests the possibility for selective activation of TRPC5 channels by xanthine derivatives and supports the general principle that xanthine‐based small molecules can activate, potentiate or inhibit these channels depending on subunit composition.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 The Authors British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) (https://creativecommons.org/licenses/by/4.0/) |
Keywords: | Calcium channels; cation channels; TRP channels; xanthines |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) The University of Leeds > Faculty of Engineering & Physical Sciences (Leeds) > School of Chemistry (Leeds) > Organic Chemistry (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Funding Information: | Funder Grant number BBSRC BB/P020208/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 10 Jul 2019 10:44 |
Last Modified: | 07 Jun 2023 13:59 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1111/bph.14791 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:148366 |