Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q86TM3 (cage)
 29,987 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Radioligand binding studies indicate that p-isothiocyanato-t-butylbicycloorthobenzoate (p-NCS-TBOB) specifically acylates GABA-gated chloride channels. Preincubation of synaptoneurosomes with p-NCS-TBOB followed by washing resulted in a concentration dependent (63-500 nM) inhibition of both muscimol-stimulated chloride uptake and [355]t-butylbicyclophosphorothionate (TBPS) binding. The extent of acylation (assessed by inhibition of [35S]TBPS binding) was highly correlated (r = 0.89; p less than 0.001) with the inhibition of muscimol-stimulated Cl- uptake. Neither basal Cl- uptake nor [3H]muscimol binding to GABAA receptors were affected by p-NCS-TBOB. Preincubation with the nonacylating 'cage' convulsant t-butylbicycloorthobenzoate (500 nM) followed by washing had no effect on either muscimol-stimulated Cl- uptake or [35S]TBPS binding. These findings indicate that p-NCS-TBOB interferes with the efficacy of muscimol promoted channel openings, but does not affect the recognition qualities of GABAA receptors. p-NCS-TBOB should prove useful in electrophysiological and biochemical studies examining the properties of GABA-gated Cl- channels.
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PMID:Site-specific acylation of GABA-gated Cl- channels: effects on 36Cl- uptake. 171 8

Attacks of sustained dystonic postures of limbs and trunk can be initiated by handling or mild environmental stimuli (e.g. new cage) in an inbred line of Syrian hamsters. The severity of the dystonic syndrome in these mutant hamsters (gene symbol dtsz) is age-dependent, with a peak at about 30-40 days of age. A scoring system for grading type and severity of the dystonic attacks can be used to study the activity of drugs against dystonic movements with individual pre- and post-drug vehicle trials as control. In the present experiments, the effects of drugs which alter GABAergic functions in the brain were studied in dystonic hamsters. Anticonvulsants, i.e. valproate, diazepam and phenobarbital, which augment GABAergic neurotransmission, decreased the severity of dystonic attacks in the mutant hamsters, while administration of subconvulsive doses of pentylenetetrazol or the inverse benzodiazepine receptor agonist FG 7142 increased the severity of the syndrome. Anticonvulsants, i.e. phenytoin and carbamazepine, which are not thought to act via effects on GABAergic neurotransmission, exerted no antidystonic effects, but even worsened the attack in several animals. In contrast, the GABA-elevating drug, aminooxyacetic acid, produced a marked antidystonic effect in the hamsters. Similarly, the GABAB receptor agonist, baclofen, significant decreased the severity of the dystonic attack. The data indicate that dystonic movements in dtsz mutant hamsters can be attenuated by drugs which facilitate GABAergic functions, but worsened by drugs which impair GABAergic neurotransmission. These data thus seem to suggest that the dystonic syndrome in dtsz mutant hamsters is under GABAergic influence. The data show furthermore that dystonic hamsters are a suitable model to detect antidystonic effects of drugs.
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PMID:Effects of pharmacological manipulation of GABAergic neurotransmission in a new mutant hamster model of paroxysmal dystonia. 185 2

The biochemical mechanism responsible for the convulsive effects of folates was investigated. The epileptogenic effects of folates were determined in vivo by quantification of the seizures following intracortical application in rats. The rank order of epileptogenic effects is: folic acid greater than or equal to 5-HCO-H4 folate greater than H2 folate greater than 5-CH3-H4 folate. This sequence of epileptogenicity in vivo is compared to the rank order of the effects of folates on radioligand binding to the GABAA-receptor complex in vitro. The inhibitory potencies of folates on [3H]muscimol and [3H]diazepam bindings did not correlate with their epileptogenic effects. However, folates reverse the inhibiting effect of GABA on the binding of the cage convulsant [3H]TBOB [( 3H]t-butylbicycloorthobenzoate). The rank order of this in vitro effect (folic acid greater than 5-HCO-H4 folate greater than H2 folate = 5-CH3-H4 folate) resembles the rank order of epileptogenicity determined in vivo. A relationship between the in vivo and in vitro effects is therefore suggested.
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PMID:Folates: epileptogenic effects and enhancing effects on [3H]TBOB binding to the GABAA-receptor complex. 216 59

[35S]t-Butylbicyclophosphorothionate ([35S]TBPS), a bicyclic cage convulsant, binds to the anion gating mechanism of the GABA/benzodiazepine receptor chloride channel complex. Using a carefully calibrated radiation inactivation technique, the molecular weight of [35S]TBPS binding complexes from frozen rat cerebral cortex was estimated to be 137,000 daltons. The GABA agonist muscimol reduced [35S]TBPS binding to 0-10% of the control value, in a way which is independent of the radiation dose. This shows that the GABA receptor (Mw = 55,000 daltons) is included in the 137,000-dalton [35S]-TBPS binding complex; the [35S]TBPS binding protein alone accounts for 137,000-55,000 = 82,000 daltons. The pyrazolopyridazine etazolate (SQ 20.009) and etomidate in appropriate concentrations both reduced specific binding of [35S]TBPS. The ability of SQ 20.009 and etomidate to reduce [35S]TBPS binding was greatly reduced by exposure to low radiation doses, suggesting that SQ 20.009 and etomidate reduce [35S]TBPS binding by an allosteric mechanism requiring a molecular structure of 450,000-500,000 daltons. Benzodiazepine agonists (ethyl 4-methoxymethyl-6-benzyloxy-beta-carboline-3-carboxylate, ZK 93423) and inverse agonists (methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate, DMCM) enhance and reduce [35S]TBPS binding, respectively, in repeatedly frozen and washed membrane preparations. The effects of ZK 93423 and DMCM on [35S]TBPS binding disappeared upon exposure of membranes to low radiation doses. This suggests that the benzodiazepine receptor site interacts allosterically with the [35S]TBPS binding site, requiring a molecular complex of at least c. 400,000 daltons. The [35S]TBPS site alone in these latter conditions of membrane preparation (repeatedly frozen/washed) revealed a molecular weight of 221,000 daltons (TBPS-site + GABA receptor + unknown structures). The number of binding sites for [35S]TBPS (145 pmol/g tissue) was only slightly higher than for [3H]flunitrazepam (130 pmol/g tissue) in cerebral cortex. These results are all consonant with the conclusion that the GABA/BZ receptor chloride channel complex is composed of highly integrated multimeric subunits, tentatively accounted for by a tetramic complex of molecular weight 548,000 daltons.
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PMID:Radiation inactivation of brain [35S]t-butylbicyclophosphorothionate binding sites reveals complicated molecular arrangements of the GABA/benzodiazepine receptor chloride channel complex. 241 62

The meta- and para-isothiocyanato derivatives of t-butylbicycloorthobenzoate (TBOB) were synthesized by catalytic reduction of the corresponding nitro compounds, followed by treatment with thiophosgene. p-NCS-TBOB (2) inhibited the binding of both [3H]TBOB and [35S]t-butylbicyclophosphorothionate (TBPS) with potencies (IC50 of 61 and 23 nM, respectively) similar to the parent compound. In contrast, the meta derivative (m-NCS-TBOB, 1) was more than 1 order of magnitude less potent (IC50 of 1588 and 149 nM, respectively). The IC50 values for both 1 and 2 were strongly dependent on the tissue concentration, in a manner characteristic of irreversible inhibitors. Moreover, preincubation of tissue with these compounds, followed by extensive washing, resulted in a concentration-dependent reduction in the number of [35S]TBPS binding sites and in the apparent affinity of this radioligand. Similar effects were not observed in tissues treated in identical fashion with either TBOB or picrotoxin. Preincubation with p-NCS-TBOB at concentrations that significantly inhibit [35S]TBPS or [3H]TBOB binding did not affect radioligand binding to either benzodiazepine or gamma-aminobutyric acid receptors. These findings suggest that m- and p-NCS-TBOB bind irreversibly to sites labeled by cage convulsants such as TBOB and TBPS, which are on or near GABA-gated chloride channels. p-NCS-TBOB should prove useful in determining the molecular characteristics of the benzodiazepine receptor-coupled GABA-gated chloride ionophore.
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PMID:meta- and para-isothiocyanato-t-butylbicycloorthobenzoate: irreversible ligands of the gamma-aminobutyric acid-regulated chloride ionophore. 253 56

1. Using homogenates of supraoesophageal ganglia from locust we observed specific binding of [35S]-TBPS which was linear with protein concentration up to 7 mg/ml, showed a pH optimum at pH 9.0 and was linear with NaCl concentration up to 350 mM. 2. Kinetic analysis of the binding showed positive cooperativity as a result of changes in on and off-rates with occupation of the binding site by the ligand. The apparent KD = 417 nM and Bmax = 1083 fmol/mg of membrane protein were calculated using a computer program for dose-response curve fitting. 3. The binding was enhanced by GABA, pentobarbital and benzodiazepines. Picrotoxinin had no effect on the binding at 0.1 mM. Only the cage convulsants TBPS and IBP were able to displace the binding. 4. Whilst the characteristics of the binding are similar to those reported for house fly thorax and abdomen preparations they are significantly different from those reported for house fly head, cockroach nerve cord and rat brain.
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PMID:Further characterisation of the [35S]-TBPS binding site of the GABA receptor complex in locust (Schistocerca gregaria) ganglia membranes. 256 51

The site of action responsible for the convulsive effect of folic acid was investigated in vitro. Folic acid (ECmax 5 x 10(-4) M) enhances the binding of the cage convulsant [3H]t-butylbicycloorthobenzoate ([3H]TBOB) to rat brain membranes, namely to 130% of control in the absence of GABA and to over 300% of control in the presence of physiological concentrations of GABA. Analysis of the binding parameters reveals that folic acid increases the apparent number of [3H]TBOB binding sites.
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PMID:The influence of folic acid on the picrotoxin-sensitive site of the GABAa-receptor complex. 284 98

gamma-Aminobutyric acid (GABA) stimulated 36Cl- influx into membrane vesicles from rat cerebral cortex at 3 to 300 microM in a concentration-dependent manner with near maximum response at 100 microM. Inhibitory potencies for this GABA (100 microM)-dependent 36Cl- uptake were determined for 16 cage convulsants including 10 bicycloorthocarboxylates and 3 bicyclophosphorus esters and for 8 polychlorocycloalkane insecticides. Inhibition by derivatives of t-butylbicycloorthobenzoate (TBOB) and t-butylbicyclophosphorothionate (TBPS) depended on the substituents at both positions 1 and positions 4. Among them, the 4-cyano-phenyl analog of TBOB was the most potent inhibitor with an IC50 value of 40 nM. Other cage convulsants such as picrotoxinin, tetramethylenedisulfotetramine and p-chlorophenylsilatrane were less potent than TBOB and TBPS. The potencies of bicycloorthocarboxylates, bicyclophosphorus esters and other cage convulsants in inhibiting GABA-stimulated 36Cl- uptake by rat cerebral cortex were significantly correlated with those in inhibiting [35S]TBPS binding to the human and mouse brain receptors (r = 0.96, P less than .01). There also was a significant correlation between the potencies of the polychlorocycloalkanes examined in inhibiting GABA-stimulated 36Cl- uptake and [35S]TBPS binding to the mouse brain receptor (r = 0.94, P less than .01). In these correlations, the polychlorocycloalkanes appear to fall on a different line than that for the bicycloorthocarboxylates, bicyclophosphorus esters and other cage convulsants. Both the cage convulsants and the polychlorocycloalkanes are considered to act at convulsant sites coupled functionally to the GABA receptor chloride ionophore complex and thereby to modulate allosterically or directly the GABA-gated chloride channel leading to their toxic action.
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PMID:Modulation of gamma-aminobutyric acid-stimulated chloride influx by bicycloorthocarboxylates, bicyclophosphorus esters, polychlorocycloalkanes and other cage convulsants. 285 43

Both barbiturates and ethanol have been reported to interact with the GABA-benzodiazepine receptor-chloride ionophore 'supramolecular complex'. These observations raise the possibility that some of the pharmacologic actions of barbiturates and ethanol may be mediated through this complex. In this study we have administered a series of drugs which bind to various components of the complex in an attempt to antagonize the lethality of sodium pentobarbital, and ethanol-induced loss of righting reflex in mice. It was found that isopropylbicyclophosphate (IPPO), a cage convulsant which binds at or near the chloride ionophore, greatly reduces the overall mortality (and increases latency to death) of animals pretreated with a lethal dose of pentobarbital. Picrotoxin also decreases pentobarbital lethality, but only at doses which were usually lethal when given alone. Picrotoxin shortened, rather than increased, latency to death. Strychnine did not prevent pentobarbital lethality, suggesting that the IPPO effect is not shared by convulsants in general. IPPO did not prevent ketamine-induced deaths, which supports the notion that the protective actions of IPPO are specific for depressant drugs which act at the chloride ionophore. IPPO also significantly reduced the duration of loss of righting reflex induced by ethanol. These observations suggest that the use of compounds which have a high affinity for the chloride ionophore in vitro might be fruitful in developing a clinical treatment for barbiturate or ethanol toxicity.
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PMID:Are the toxicities of pentobarbital and ethanol mediated by the GABA-benzodiazepine receptor-chloride ionophore complex? 298 19

The involvement of central GABAergic mechanisms in the control over offensive and defensive behaviours in the rat was studied using intracerebroventricular injections (5 microliter) of a GABA agonist (THIP) or a GABA antagonist (bicuculline methiodide). Intracerebroventricular injections of THIP (1.25 and 2.5 micrograms) induced attacks and offensive sideways towards an untreated partner, in animals placed in a neutral area where no aggressive reactions occur in controls. Social approach behaviours (partner investigation, allogrooming) were also increased in both attacking and non-attacking animals, whereas individual behaviours (cage exploration, autogrooming, immobile posture) were decreased. Inversely, intracerebroventricular injections of bicuculline methiodide (62.5 and 125 ng) suppressed offensive items (attacks, offensive sideways, upright postures) in resident animals confronted with untreated intruders and increased occurrence of defensive sideways. This treatment also decreased reactions oriented towards the partner (investigation, allogrooming and crawl under/over), while increasing individual behaviours (cage exploration, immobile posture). These data demonstrate that activation of central GABA receptors elicits intraspecific offensive behaviours in the rat. On the contrary, blockage of these receptors induces defensive reactions and suppresses offensive behaviours. The involvement of these receptors in the neural control over aggressive behaviour in the rat is discussed.
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PMID:Elicitation of conspecific attack or defense in the male rat by intraventricular injection of a GABA agonist or antagonist. 299 44


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