Molecular pharmacology
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Molecular pharmacology · Jun 2017
Halogenated Ether, Alcohol, and Alkane Anesthetics Activate TASK-3 Tandem Pore Potassium Channels Likely through a Common Mechanism.
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 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.