RT Journal Article
SR Electronic
T1 A small molecular compound selectively activates K2P channel TASK-3 by acting at two distant clusters of residues
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.118.115303
DO 10.1124/mol.118.115303
A1 Fuyun Tian
A1 Yunguang Qiu
A1 Xi Lan
A1 Min Li
A1 Huaiyu Yang
A1 Zhaobing Gao
YR 2019
UL http://molpharm.aspetjournals.org/content/early/2019/04/23/mol.118.115303.abstract
AB TASK-3 channel is a member of the K2P family that important for the maintenance of the resting membrane potential. Previous studies have demonstrated that TASK-3 channel was involved in several physiological and pathological processes including sleep/wake control, cognition and epilepsy. However, there is still a lack of selective pharmacological tools of TASK-3 currently, which limits the further research of channel function. In this work, we discovered N-(2-((4-nitro-2-(trifluoromethyl)phenyl)amino)ethyl)benzamide (NPBA) as a novel TASK-3 activator using high-throughput screen (HTS), which showed excellent potency and selectivity. The molecular determinants of NPBA activation were then investigated by combining chimera and mutagenesis analysis. Two distant clusters of residues, locating at extracellular end of the second transmembrane domain (TM2) (A105 and A108) and the intracellular end of the fourth transmembrane domain (TM3) (E157), respectively, were identified to be critical for NPBA activation. We then compared essentials of the actions of NPBA with inhalation anesthetics which activate TASK-3 non-selectively and found that they may activate TASK-3 channel through different mechanisms. Finally, by transplanting the three residues, A105, A108 and E157, into TASK-1 channel which resists to NPBA activation, the constructed mutant TASK-1(G105A, V108A, A157E) dramatically gained the activation by NPBA, which confirms the importance of these two distant clusters of residues.