TY - JOUR T1 - Halogenated ether, alcohol, and alkane anesthetics activate TASK-3 tandem pore potassium channels likely through a common mechanism JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.117.108290 SP - mol.117.108290 AU - Anita Luethy AU - James D. Boghosian AU - Rithu Srikantha AU - Joseph F. Cotten Y1 - 2017/01/01 UR - http://molpharm.aspetjournals.org/content/early/2017/04/06/mol.117.108290.abstract N2 - TASK-3 (KCNK9) tandem pore potassium channel function is activated by halogenated anesthetics through binding at a putative anesthetic binding cavity. To understand pharmacological requirements for TASK-3 activation, we studied the concentration-response of TASK-3 to several anesthetics (isoflurane, desflurane, sevoflurane, halothane, α-chloralose, 2,2,2-trichloroethanol(TCE), and chloral hydrate), to ethanol, and to a panel of halogenated methanes and alcohols. We used mutagenesis to probe the anesthetic binding cavity as observed in a TASK-3 homology model. METHODS: TASK-3 activation was quantified by Ussing chamber voltage clamp analysis. We mutagenized residue Val-136, which lines the anesthetic binding cavity, its flanking residues (132 to 140), and Leu-122, a pore gating residue. RESULTS: 2-halogenated ethanols activate wild-type TASK-3 with the rank order efficacy (normalized current [95% confidence]): 2,2,2-tribromo-(267%[240-294]) > 2,2,2-trichloro-(215%[196-234]) > chloral hydrate(165%[161-176]) > 2,2-dichloro- > 2-chloro ≈ 2,2,2-trifluoroethanol > ethanol. Similarly, carbon tetrabromide(296%[245-346]), carbon tetrachloride(180%[163-196]) and 1,1,1,3,3,3-hexafluoropropanol(200%[194-206]) activate TASK-3, whereas the larger carbon tetraiodide and α-chloralose inhibit. Clinical agents activate TASK-3 with the following rank order efficacy: halothane(207%[202-212]) > isoflurane(169%[161-176]) > sevoflurane(164%[150-177]) > desflurane(119%[109-129]). Mutations at and near residue-136 modify TCE activation of TASK-3, and; interestingly, M159W, V136E, and L122D, were resistant to both isoflurane and TCE activation. CONCLUSIONS: TASK-3 function is activated by multiple agents and requires a halogenated substituent between ~30 and 232 cm3/mol volume with potency increased by halogen polarizeability. Val-136 and adjacent residues may mediate anesthetic binding and stabilize an open state regulated by pore residue Leu-122. Isoflurane and TCE likely share commonalities in their mechanism of TASK-3 activation. ER -