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[PMID]: | 24509840 |
[Au] Autor: | Veale EL; Al-Moubarak E; Bajaria N; Omoto K; Cao L; Tucker SJ; Stevens EB; Mathie A |
[Ad] Endereço: | Medway School of Pharmacy, University of Kent, Chatham Maritime, Kent, United Kingdom (E.L.V., E.A.-M., N.B., A.M.); Pfizer Neusentis, Great Abington, Cambridge, United Kingdom (K.O., L.C., E.B.S.); and Clarendon Laboratory, Department of Physics, University of Oxford, Oxford, United Kingdom (S.J.T.). |
[Ti] Título: | Influence of the N terminus on the biophysical properties and pharmacology of TREK1 potassium channels. |
[So] Source: | Mol Pharmacol;85(5):671-81, 2014 May. | [Is] ISSN: | 1521-0111 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | TWIK-related K(+) 1 (TREK1) potassium channels are members of the two-pore domain potassium channel family and contribute to background potassium conductances in many cell types, where their activity can be regulated by a variety of physiologic and pharmacologic mediators. Fenamates such as FFA (flufenamic acid; 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid), MFA [mefenamic acid; 2-(2,3-dimethylphenyl)aminobenzoic acid], NFA [niflumic acid; 2-{[3-(trifluoromethyl)phenyl]amino}nicotinic acid], and diclofenac [2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid] and the related experimental drug BL-1249 [(5,6,7,8-tetrahydro-naphthalen-1-yl)-[2-(1H-tetrazol-5-yl)-phenyl]-amine] enhance the activity of TREK1 currents, and we show that BL-1249 is the most potent of these compounds. Alternative translation initiation produces a shorter, N terminus truncated form of TREK1 with a much reduced open probability and a proposed increased permeability to sodium compared with the longer form. We show that both forms of TREK1 can be activated by fenamates and that a number of mutations that affect TREK1 channel gating occlude the action of fenamates but only in the longer form of TREK1. Furthermore, fenamates produce a marked enhancement of current through the shorter, truncated form of TREK1 and reveal a K(+)-selective channel, like the long form. These results provide insight into the mechanism of TREK1 channel activation by fenamates, and, given the role of TREK1 channels in pain, they suggest a novel analgesic mechanism for these compounds. |
[Mh] Termos MeSH primário: |
Fenamatos/farmacologia Canais de Potássio de Domínios Poros em Tandem/agonistas Canais de Potássio de Domínios Poros em Tandem/fisiologia
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[Mh] Termos MeSH secundário: |
Células HEK293 Seres Humanos Ativação do Canal Iônico/efeitos dos fármacos Ativação do Canal Iônico/fisiologia Mutação/fisiologia Canais de Potássio de Domínios Poros em Tandem/química Estrutura Secundária de Proteína
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[Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (Fenamates); 0 (Potassium Channels, Tandem Pore Domain); 0 (potassium channel protein TREK-1) |
[Em] Mês de entrada: | 1405 |
[Cu] Atualização por classe: | 150708 |
[Lr] Data última revisão:
| 150708 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 140211 |
[St] Status: | MEDLINE |
[do] DOI: | 10.1124/mol.113.091199 |
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