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

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

Walsh, Yvonne, Leach, Michael ORCID: 0000-0002-9859-1325, Veale, Emma and Mathie, Alistair (2021) Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine, and CEN-092. Biochemistry and Biophysics Reports, 26:101021. ISSN 2405-5808 (doi:https://doi.org/10.1016/j.bbrep.2021.101021)

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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-diamino-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 isoform 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 lamotrigine 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 inhibitor 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
Uncontrolled Keywords: TREK channel, TRESK channel, K2P cannel, lamotrigine, Sipatrigine, CEN-092
Subjects: Q Science > Q Science (General)
Faculty / Department / Research Group: Faculty of Engineering & Science
Faculty of Engineering & Science > Biomedical Science Research Group
Faculty of Engineering & Science > School of Science (SCI)
Last Modified: 08 Jun 2021 10:10
Selected for GREAT 2016: None
Selected for GREAT 2017: None
Selected for GREAT 2018: None
Selected for GREAT 2019: None
Selected for REF2021: None
URI: http://gala.gre.ac.uk/id/eprint/32809

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