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The actions of ether, alcohol and alkane general anaesthetics on GABA A and glycine receptors and the effects of TM2 and TM3 mutations

2000; Wiley; Volume: 129; Issue: 4 Linguagem: Inglês

10.1038/sj.bjp.0703087

1476-5381

Matthew D. Krasowski, Neil L. Harrison,

Ion channel regulation and function

The actions of 13 general anaesthetics (diethyl ether, enflurane, isoflurane, methoxyflurane, sevoflurane, chloral hydrate, trifluoroethanol, tribromoethanol, tert ‐butanol, chloretone, brometone, trichloroethylene, and α‐chloralose) were studied on agonist‐activated Cl − currents at human GABA A α 2 β 1 , glycine α 1 , and GABA C ρ 1 receptors expressed in human embryonic kidney 293 cells. All 13 anaesthetics enhanced responses to submaximal (EC 20 ) concentrations of agonist at GABA A and glycine receptors, except α‐chloralose, which did not enhance responses at the glycine α 1 receptor. None of the anaesthetics studied potentiated GABA responses at the GABA C ρ 1 receptor. Potentiation of submaximal agonist currents by the anaesthetics was studied at GABA A and glycine receptors harbouring mutations in putative transmembrane domains 2 and 3 within GABA A α 2 , β 1 , or glycine α 1 receptor subunits: GABA A α 2 (S270I)β 1 , α 2 (A291W)β 1 , α 2 β 1 (S265I), and α 2 β 1 (M286W); glycine α 1 (S267I) and α 1 (A288W). For all anaesthetics studied except α‐chloralose, at least one of the mutations above abolished drug potentiation of agonist responses at GABA A and glycine receptors. α‐Chloralose produced efficacious direct activation of the GABA A α 2 β 1 receptor (a ‘GABA‐mimetic’ effect). The other 12 anaesthetics produced minimal or no direct activation of GABA A and glycine receptors. A non‐anaesthetic isomer of α‐chloralose, β‐chloralose, was inactive at GABA A and glycine receptors and did not antagonize the actions of α‐chloralose at GABA A receptors. The implications of these findings for the molecular mechanisms of action of general anaesthetics at GABA A and glycine receptors are discussed. British Journal of Pharmacology (2000) 129 , 731–743; doi: 10.1038/sj.bjp.0703087