title: Influence of the N terminus on the biophysical properties and pharmacology of TREK1 potassium channels.
abstract: 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.
authors: 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.).
authors: Emma L
authors: EL
authors: Veale
authors: Ehab
authors: E
authors: Al-Moubarak
authors: Naina
authors: N
authors: Bajaria
authors: Kiyoyuki
authors: K
authors: Omoto
authors: Lishuang
authors: L
authors: Cao
authors: Stephen J
authors: SJ
authors: Tucker
authors: Edward B
authors: EB
authors: Stevens
authors: Alistair
authors: A
authors: Mathie
mesh_terms: D054361:Fenamates / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D009154:Mutation / Q000502:physiology; D024683:Potassium Channels, Tandem Pore Domain / Q000819:agonists* / Q000737:chemistry / Q000502:physiology*; D017433:Protein Structure, Secondary
chemical_list: D054361:Fenamates; D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1