Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092
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 derivativ...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-07-01
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| Series: | Biochemistry and Biophysics Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405580821001163 |
| _version_ | 1818622202111590400 |
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| author | Yvonne Walsh Michael Leach Emma L. Veale Alistair Mathie |
| author_facet | Yvonne Walsh Michael Leach Emma L. Veale Alistair Mathie |
| author_sort | Yvonne Walsh |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-16T18:21:25Z |
| format | Article |
| id | doaj.art-4f921aa9afae4c03aa88615f89c1e064 |
| institution | Directory Open Access Journal |
| issn | 2405-5808 |
| language | English |
| last_indexed | 2024-12-16T18:21:25Z |
| publishDate | 2021-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biochemistry and Biophysics Reports |
| spelling | doaj.art-4f921aa9afae4c03aa88615f89c1e0642022-12-21T22:21:33ZengElsevierBiochemistry and Biophysics Reports2405-58082021-07-0126101021Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092Yvonne Walsh0Michael Leach1Emma L. Veale2Alistair Mathie3Medway School of Pharmacy, University of Kent and University of Greenwich, Central Avenue, Chatham Maritime, ME4 4TB, UK; University of Greenwich, Central Avenue, Chatham Maritime, ME4 4TB, UKUniversity of Greenwich, Central Avenue, Chatham Maritime, ME4 4TB, UKMedway School of Pharmacy, University of Kent and University of Greenwich, Central Avenue, Chatham Maritime, ME4 4TB, UKMedway School of Pharmacy, University of Kent and University of Greenwich, Central Avenue, Chatham Maritime, ME4 4TB, UK; School of Engineering, Arts, Science and Technology, University of Suffolk, Waterfront Building, Neptune Quay, Ipswich, IP4 1QJ, UK; Corresponding author.Medway School of Pharmacy, University of Kent and University of Greenwich, Central Avenue, Chatham Maritime, ME4 4TB, UK.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.http://www.sciencedirect.com/science/article/pii/S2405580821001163TREK channelTRESK channelK2P channelLamotrigineSipatrigineCEN-092 |
| spellingShingle | Yvonne Walsh Michael Leach Emma L. Veale Alistair Mathie Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092 Biochemistry and Biophysics Reports TREK channel TRESK channel K2P channel Lamotrigine Sipatrigine CEN-092 |
| title | Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092 |
| title_full | Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092 |
| title_fullStr | Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092 |
| title_full_unstemmed | Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092 |
| title_short | Block of TREK and TRESK K2P channels by lamotrigine and two derivatives sipatrigine and CEN-092 |
| title_sort | block of trek and tresk k2p channels by lamotrigine and two derivatives sipatrigine and cen 092 |
| topic | TREK channel TRESK channel K2P channel Lamotrigine Sipatrigine CEN-092 |
| url | http://www.sciencedirect.com/science/article/pii/S2405580821001163 |
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