Halogenated Ether, Alcohol, and Alkane Anesthetics Activate TASK-3 Tandem Pore Potassium Channels Likely through a Common Mechanism
| Autor: | James D. Boghosian, Rithu Srikantha, Joseph F. Cotten, Anita Luethy |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Halogenation Saccharomyces cerevisiae Medicinal chemistry Ether Sevoflurane Protein Structure Secondary 03 medical and health sciences chemistry.chemical_compound Desflurane Potassium Channels Tandem Pore Domain Alkanes medicine Organic chemistry Animals Cells Cultured Pharmacology Ethanol Binding Sites Dose-Response Relationship Drug Halogenated ether Articles Potassium channel Rats Inbred F344 Protein Structure Tertiary Rats 030104 developmental biology chemistry Isoflurane Anesthetic Anesthetics Inhalation Molecular Medicine Halothane medicine.drug |
| Popis: | The TWIK-related acid-sensitive potassium channel 3 (TASK-3; KCNK9) tandem pore potassium channel function is activated by halogenated anesthetics through binding at a putative anesthetic-binding cavity. To understand the pharmacologic 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. TASK-3 activation was quantified by Ussing chamber voltage clamp analysis. We mutagenized the residue Val-136, which lines the anesthetic-binding cavity, its flanking residues (132 to 140), and Leu-122, a pore-gating residue. The 2-halogenated ethanols activate wild-type TASK-3 with the following rank order efficacy (normalized current [95% confidence interval]): 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. TASK-3 function is activated by a 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. |
| Databáze: | OpenAIRE |
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