Fenamates and diltiazem modulate lipid-sensitive mechano-gated 2P domain K(+) channels

• Published in: Pflügers Archiv 2005-12, Vol.451 (3), p.474-478
• Main Authors: Takahira, Masayuki, Sakurai, Mayumi, Sakurada, Norimasa, Sugiyama, Kazuhisa
• Format: Article
• Language: English
• Subjects: Animals; Cercopithecus aethiops; COS Cells; Diltiazem - pharmacology; Epithelium, Corneal - physiology; Gene Expression; Humans; Lipids; Lipids - physiology; ortho-Aminobenzoates - pharmacology; Potassium Channels, Tandem Pore Domain - drug effects; Potassium Channels, Tandem Pore Domain - physiology; Transfection
• ISSN: 0031-6768; 1432-2013
• DOI: 10.1007/s00424-005-1492-5

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.