Mode of action of ICS 205,930, a novel type of potentiator of responses to glycine in rat spinal neurones

Abstract

1 The e ect of a novel potentiator of glycine responses, ICS 205,930, was studied by whole-cell recordings from spinal neurones, and compared with that of other known potentiators, in an attempt to di erentiate their sites of action. 2 The ability of ICS 205,930 (0.2 mM) to potentiate glycine responses persisted in the presence of concentrations of Zn 2+ (5 ± 10 mM) that were saturating for the potentiating e ect of this ion. 3 Preincubation with 10 mM Zn 2+ before application of glycine plus Zn 2+ had an inhibitory e ect, which did not result from Zn 2+ entry into the neurone, since it persisted with either 10 mM internal EGTA or 10 mM internal Zn 2+ . To test whether the potentiating e ects of ICS 205,930 and Zn 2+ interact, both compounds were applied without preincubation. 4 The potentiating e ect of ICS 205,930 was similar for responses to glycine and for responses to glycine plus Zn 2+ , provided the concentrations of agonist were adjusted so as to induce control responses of identical amplitudes. 5 ICS 205,930 remained able to potentiate glycine responses in the presence of ethanol (200 mM). 6 ICS 205,930 also retained its potentiating e ect in the presence of the anaesthetic propofol (30 ± 90 mM), which strongly potentiated glycine responses but, in contrast with ICS 205,930, also markedly increased the resting conductance. 7 The anticonvulsant chlormethiazole (50 ± 100 mM) neither potentiated glycine responses nor prevented the e ect of ICS 205,930, even though it increased the resting conductance and potentiated GABA A responses. 8 The mechanism of action of ICS 205,930 appears to be di erent from those by which Zn 2+ , propofol or ethanol potentiate glycine responses.

An Electrophysiological Study Of The Effects Of Propofol On Native Neuronal Ligand-Gated Ion Channels

“…[44][45][46] Consistent with this hypothesis, propofol enhances submaximal (EC2-EC20) glycine-evoked responses recorded from recombinant receptors expressed in oocytes 46,47 and glycine-evoked currents recorded from cultured spinal neurons. 7,36 In contrast, Hara et al 8,9 observed neither direct activation nor modulation of glycine receptor currents recorded from acutely dissociated rat hippocampal neurons with propofol (1 and 5 mol/L). Our own data show that while glycine-evoked responses in the optic nerve were potentiated by propofol (which was modest when compared with GABA response modulation) we observed no effect on the strychninesensitive glycine current responses recorded from rat cultured embryonic hippocampal neurons, even at a concentration maximally effective for potentiation of the GABAA current and twice that investigated by Hara et al 9 Higher (supra-anaesthetic) concentrations of propofol may modulate glycine receptors in hippocampal neurons but because they also directly activated the GABAA receptor 10 and resulted in desensitization of the GABA response, we did not examine these concentrations further.…”

Molecular Pharmacology of the Glycine Receptor Chloride Channel

“…Structure-activity analyses of tropisetron analogues have provided some insight into the tropisetron structural moieties required for potentiation and inhibition [134][135][136][137][138][139][140][141]. One such analysis concluded that an aromatic ring, a carbonyl group and a tropane nitrogen are required for glycinergic potentiation [134].…”

Potentiation of glycine responses by dideoxyforskolin and tamoxifen in rat spinal neurons

“…Glycine receptors also contain modulatory sites. For example, glycine responses can be potentiated by alcohols, different types of anaesthetics (Belelli et al ., 1999; Krasowski & Harrison, 1999), inhaled drugs of abuse (Beckstead et al ., 2000), Zn 2+ (Bloomenthal et al ., 1994; Laube et al ., 1995; Lynch et al ., 1998; Suwa et al ., 2001), some 5‐HT 3 antagonists (Chesnoy‐Marchais, 1996; Chesnoy‐Marchais, 1999; Chesnoy‐Marchais et al ., 2000; Supplisson & Chesnoy‐Marchais, 2000) and some dihydropyridines (DHPs; Chesnoy‐Marchais & Cathala, 2001). Some of these potentiators interact with transmembrane segments (Belelli et al ., 1999; Krasowski & Harrison, 1999; Beckstead et al ., 2000; Mascia et al ., 2000).…”