Fenamates and diltiazem modulate lipid-sensitive mechano-gated 2P domain K(+) channels.
A swelling-activated, background K(+) current in the corneal epithelium is characteristically activated by fenamates and inhibited by diltiazem. Fatty acids also stimulate this current, indicating that its origin is a lipid-sensitive mechano-gated 2P domain K(+) channel. In the present study, modulation of TREK-1, TREK-2, and TRAAK channels by fenamates and diltiazem was examined. TREK-1, TREK-2, and TRAAK currents transiently expressed in COS-7 cells were recorded by the perforated-patch configuration. As previously reported, arachidonic acid (20 microM) stimulated all of these channels, and a volatile anesthetic, halothane (1 mM) augmented TREK-1 and TREK-2 but not TRAAK. Flufenamic acid (FA, 100 microM), niflumic acid (NA, 100 microM), and mefenamic acid (MA, 100 microM) markedly stimulated TREK-1, TREK-2, and TRAAK. The potency sequence for the activation of TREK-1 and TREK-2 was FA > NA = MA, and the potency sequence for the activation of TRAAK was FA = NA > MA. Diltiazem (1 mM) inhibited TREK-1 and TREK-2, but not TRAAK. In conclusion, fenamates are openers of the lipid-sensitive mechano-gated 2P domain K(+) channels, and diltiazem may be a specific blocker for TREK. These novel findings could help to further understand channel functions of the mechano-gated 2P domain K(+) channels.
Takahira
Masayuki
M
Department of Visual Neuroscience and Ophthalmology, Kanazawa University, Takara-Machi 13-1, Kanazawa 920-8640, Japan. takahira@kenroku.kanazawa-u.ac.jp
Sakurai
Mayumi
M
Sakurada
Norimasa
N
Sugiyama
Kazuhisa
K
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004110:Diltiazem / Q000494:pharmacology*; D019573:Epithelium, Corneal / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D008055:Lipids / Q000502:physiology; D024683:Potassium Channels, Tandem Pore Domain / Q000187:drug effects* / Q000502:physiology*; D014162:Transfection; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
D008055:Lipids; D024683:Potassium Channels, Tandem Pore Domain; D062367:ortho-Aminobenzoates; C001209:fenamic acid; D004110:Diltiazem