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Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092

Walsh, Yvonne, Leech, Michael, Veale, Emma L., Mathie, Alistair (2021) Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092. Biochemistry and Biophysics Reports, 26 . Article Number 101021. E-ISSN 2405-5808. (doi:10.1016/j.bbrep.2021.101021) (KAR id:88352)

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Official URL:
https://doi.org/10.1016/j.bbrep.2021.101021

Abstract

TREK and TRESK K2P channels are widely expressed in the nervous system, particularly in sensory neurons, where they regulate neuronal excitability. In this study, using whole-cell patch-clamp electrophysiology, we characterise the inhibitory effect of the anticonvulsant lamotrigine and two derivatives, sipatrigine and 3,5-dia-mino-6-(3,5-bistrifluoromethylphenyl)-1,2,4-triazine (CEN-092) on these channels. Sipatrigine was found to be a more effective inhibitor than lamotrigine of TREK-1, TREK-2 and TRESK channels. Sipatrigine was slightly more potent on TREK-1 channels (EC50 =16 μM) than TRESK (EC50 =34 μM) whereas lamotrigine was equally effective on TREK-1 and TRESK. Sipatrigine was less effective on a short iso-form of TREK-2, suggesting the N terminus of the channel is important for both inhibition and subsequent over- recovery. Inhibition of TREK-1 and TREK-2 channels by sipatrigine was reduced by mutation of a leucine residue associated with the norfluoxetine binding site on these channels (L289A and L320A on TREK-1 and TREK-2, respectively) but these did not affect inhibition by lamotrigine. Inhibition of TRESK by sipatrigine and lamo-trigine was attenuated by mutation of bulky phenylalanine residues (F145A and F352A) in the inner pore helix. However, phosphorylation mutations did not alter the effect of sipatrigine. CEN-092 was a more effective in-hibitor of TRESK channels than TREK-1 channels. It is concluded that lamotrigine, sipatrigine and CEN-092 are all inhibitors of TREK and TRESK channels but do not greatly discriminate between them. The actions of these compounds may contribute to their current and potential use in the treatment of pain and depression

Item Type: Article
DOI/Identification number: 10.1016/j.bbrep.2021.101021
Divisions: Divisions > Division of Natural Sciences > Medway School of Pharmacy
Depositing User: Emma Veale
Date Deposited: 09 Jun 2021 12:18 UTC
Last Modified: 04 Jul 2023 13:39 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/88352 (The current URI for this page, for reference purposes)

University of Kent Author Information

Walsh, Yvonne.

Creator's ORCID:
CReDIT Contributor Roles:

Veale, Emma L..

Creator's ORCID: https://orcid.org/0000-0002-6778-9929
CReDIT Contributor Roles:

Mathie, Alistair.

Creator's ORCID: https://orcid.org/0000-0001-6094-2890
CReDIT Contributor Roles:
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