Differential modulatory actions of the volatile convulsant flurothyl and its anesthetic isomer at inhibitory ligand-gated ion channels

Abstract

A challenge for theories of general anesthesia is the existence of compounds predicted to be anesthetics but which, instead, do not produce anesthesia and often elicit other behavioral effects such as convulsions. This study focused on flurothyl (bis[2,2,2-trifluoroethyl] ether), a potent volatile convulsant, and its anesthetic isomer, 'iso-flurothyl' (1,1,1,3,3,3-hexafluoro-2-methoxypropane). The effects of flurothyl and iso-flurothyl were studied using the whole-cell patch-clamp technique on agonist activated chloride currents in human GABA A , glycine, and GABA c ρ 1 receptors expressed in HEK 293 cells. GABA A and glycine receptors are promising molecular targets for the actions of inhaled ether general anesthetics. Flurothyl acted as a non-competitive antagonist at GABA A α 2 β 1 and α 2 β 1 γ 2s receptors, but had no effect at glycine α 1 receptors. Flurothyl had biphasic actions on GABA responses at GABA C ρ 1 receptors. In contrast, iso-flurothyl enhanced ('potentiated') submaximal agonist responses at GABA A and glycine receptors, but had no effect on GABA responses at GABA C ρ 1 receptors. Point mutations in GABA A and glycine receptor subunits, which have been previously shown to abolish potentiation of agonist responses by the ether anesthetics enflurane and isoflurane, also ablated potentiation of agonist responses by iso-flurothyl. These same mutations in the GABA A receptor had only modest effects on the inhibitory actions of flurothyl. GABA A receptors with mutations conferring insensitivity to antagonism by picrotoxin were still inhibited by flurothyl, suggesting that picrotoxin and flurothyl antagonize GABA responses by distinct sites or mechanisms of action. In summary, antagonism of GABA A receptors is likely to account for the convulsant effects of flurothyl, while the general anesthetic actions of iso-flurothyl, like those of other ether anesthetics, may be related to positive modulation of GABA A and/or glycine receptors.

Dissociated Gender-Specific Effects of Recurrent Seizures on GABA Signaling in CA1 Pyramidal Neurons: Role of GABAAReceptors

“…Finally, the difference may be model specific. Flurothyl has GABA A receptor antagonistic effects (Krasowski, 2000). Consequently, flurothyl-induced seizures may be similar to our BKB groups, which counteract the effects of 3KA-SE on E GABA .…”

Adenosine Receptor Antagonists Including Caffeine Alter Fetal Brain Development in Mice

“…Caffeine exposure increases susceptibility of mouse pups to seizures We used flurothyl, a seizure-inducing agent (39), to assess seizure susceptibility in caffeine-exposed and control offspring at P6. Pairs of caffeine-exposed/control and KW6002-exposed/control pups at P6 were exposed to flurothyl in two independent sessions (four treated and four control animals per session).…”

Positive and Negative Allosteric Modulation of an α1β3γ2 γ-Aminobutyric Acid Type A (GABAA) Receptor by Binding to a Site in the Transmembrane Domain at the γ+-β− Interface

“…Picrotoxinin, which binds at the cytoplasmic end of the ion channel (17,44), did not inhibit S- [ 3 H]mTFD-MPPB photolabeling. This establishes that in the purified ␣1␤3␥2 GABA A R, picrotoxinin binds preferentially to the same closed channel state as bicuculline, a result consistent with its allosteric inhibition of [ 3 H]azietomidate now allow the development of assays to determine whether drugs such as the volatile convulsant and GABA A R inhibitor fluorothyl (bis[2,2,2-trifluoroethy] ether) or its anesthetic isomer and GABA A R potentiator "isofluorothyl" (1,1,1,3,3,3-hexafluoro-2-methoxypropane) (4,47,48) bind selectively to intersubunit sites in the presence of bicuculline or GABA, respectively.…”