Enhancement of homomeric glycine receptor function by longchain alcohols and anaesthetics

Abstract

1 The effects of n-alcohols (ethanol to dodecanol) and anaesthetics on strychnine-sensitive glycine receptors were studied in Xenopus oocytes expressing homomeric al or a2 glycine receptor subunits, with the two electrode voltage-clamp recording technique. 2 The glycine-induced chloride conductance of homomeric a glycine receptors was potentiated by all the alcohols tested when an EC2 concentration of glycine was used. Homomeric al and a2 receptors were potentiated similarly by the n-alcohols, except that low concentrations of ethanol produced greater potentiation with acl, as previously reported. 3 Increasing the n-alcohol carbon number has been shown to increase the potency of the alcohols up to decanol at concentrations corresponding to ECsos for producing loss of righting reflex in tadpoles.However, dodecanol was no more potent than decanol, and only modest potentiation (30-60%) was obtained with dodecanol, in contrast to marked (150-200%) potentiation with the other alcohols. Thus, a 'cut-off' occurred at about dodecanol. 4 Propofol, alphaxalone, pentobarbitone, halothane and enflurane, reversibly potentiated the function of homomeric al glycine receptors at concentrations which represent approximately twice the EC50 for production of anaesthesia in mammals, but ketamine and etomidate were ineffective. 5 Two novel cyclobutane compounds were tested; the anaesthetic compound (1-chloro-1,2,2-trifluorocyclobutane) from 0.5 to 5 mm potentiated the action of glycine in a concentration-dependent manner; however, the non-anaesthetic analogue (1,2-dichloro-hexfluorocyclobutane) had no effect on glycine receptor function at concentrations (25 to 80 YM) predicted to be anaesthetic, based on the lipid solubility of this compound. 6 These results suggest that the a subunits of strychnine-sensitive glycine receptors contain sites of action for n-alcohols, propofol, alphaxalone, pentobarbitone and volatile anaesthetics, but not for ketamine and etomidate. Potentiation of glycine receptor function may contribute to the anaesthetic action of n-alcohols and volatile agents.

Identification of Novel Specific Allosteric Modulators of the Glycine Receptor Using Phage Display

“…4b). This result is in concordance with previous studies showing that other allosteric modulators of the GlyR, such as alcohols, volatile anesthetics, and low concentrations of zinc, also act by left-shifting glycine concentration-response curves (15)(16)(17).…”

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

“…For most of the non-immobilizers, the convulsant potency correlates strongly with the oil/gas partition coefficient; for the remainder, including flurothyl, this correlation does not hold . It is noteworthy that the convulsants in the first category, such as the halogenated cyclobutanes, do not appear to alter the function of any of the ligand-gated ion channels, including GABA A , glycine, and neuronal nicotinic acetylcholine receptors (Cardoso et al, 1999;Mascia et al, 1996;Mihic et al, 1994). By contrast, flurothyl and one other convulsant ether, CF 2 Cl-O-CH 2 CF 3 (M.D.…”

“…Iso-flurothyl had actions at GABA A , glycine, and GABA C ρ 1 receptors which were similar to other ether anesthetics such as isoflurane and sevoflurane (see Table 2). The ether anesthetics characterized to date have been shown to be positive allosteric modulators of GABA A and glycine receptors (Downie et al, 1996;Harrison et al, 1993;Mascia et al, 1996;Wakamori et al, 1991), while none potentiates submaximal GABA responses at the GABA C ρ 1 receptor (Harrison et al, 1993;Mihic and Harris, 1996).…”

“…These two 'inhibitory' neurotransmitter receptors are part of a ligand-gated ion channel gene superfamily that includes the nicotinic acetylcholine, serotonin 3 , and GABA C ρ receptors (Ortells and Lunt, 1995). The inhaled ether anesthetics, at clinically relevant concentrations, produce positive allosteric modulation of GABA A and glycine receptors (Downie et al, 1996;Harrison et al, 1993;Jones et al, 1992;Mascia et al, 1996;Wakamori et al, 1991). In whole-cell patch-clamp experiments, the effects of general anesthetics are evident as an enhancement ('potentiation') of submaximal current responses to agonist (reviewed by Harris et al, 1995;Krasowski and Harrison, 1999).…”

Interaction of phenol derivatives with ion channels

“…The possible importance of these lower CNS areas and hence of glycine in general anaesthesia is emphasized by a decerebration experiment, which found the minimum alveolar concentration of isoflurane to be independent of cortical and forebrain structures in the rat [42,43]. Propofol, among other general anaesthetics, has been shown to potentiate the 1 glycine receptor in vitro [44] and to directly activate heterologously expressed glycine receptors in the absence of the natural agonist. It is conceivable that other phenol derivatives might equally interfere with glycine receptor function, but no evidence exists at the present time concerning structural requirements for this effect.…”