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)

The benzodiazepine/GABA receptor coupled chloride ionophore was examined in brain membranes of rats maintained in either a conventional animal facility or a "protected" (low-stress) environment. Following a 10 min ambient temperature swim, animals maintained in both environments had qualitatively similar increases in the number (Bmax) of [35S]t-butylbicyclophosphorothionate (TBPS) binding sites, the apparent affinity of this radioligand, and the efficacy and potency of Cl- to enhance [3H]flunitrazepam binding. Nonetheless, the Bmax of [35S]TBPS and efficacy of Cl- to enhance [3H]flunitrazepam binding were significantly lower in animals housed in the protected environment compared to those maintained in a conventional facility both before and after swim stress. Furthermore, in rats housed in a protected environment, sequential removal of animals from a common cage (cohort removal), produced a very rapid increase (less than or equal to 15 s) in Cl(-)-enhanced [3H]flunitrazepam binding in cortical and hippocampal but not cerebellar membranes. Cohort removal also produced a sequential increase in the number of [35S]TBPS binding sites and apparent affinity of this radioligand in cerebral cortical membranes. The effects of cohort removal were not observed in animals subjected to ambient temperature swim or if animals were removed from different cages. Changes in the benzodiazepine/GABA receptor coupled chloride ionophore produced by cohort removal from a common cage preceded any statistically significant changes in circulating levels of alpha-MSH, beta-endorphin, ACTH or corticosterone. These findings suggest that the benzodiazepine/GABA receptor chloride ionophore complex (supramolecular complex) is under both tonic and acute regulation by the environment, and may subserve a physiologically relevant function in the response to stressful or anxiety producing stimuli.
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PMID:Environmentally-induced modification of the benzodiazepine/GABA receptor coupled chloride ionophore. 303 19

The GABA receptor of mammalian brain is a ligand-gated channel protein with allosteric binding sites for the benzodiazepines and barbiturate drugs. The receptor is an acidic oligomeric membrane glycoprotein and it has been purified to homogeneity from bovine cerebral cortex, bovine cerebellum and rat cerebral cortex by benzodiazepine affinity chromatography. In each case, extraction and purification with the zwitterionic detergent CHAPS and exogenous phospholipid has demonstrated the coexistence of GABA, benzodiazepine and cage convulsant ligand binding sites on a single protein complex; in addition the allosteric interactions between these sites are preserved in the isolated protein. The receptor has a heterologous structure that is conserved at the subunit level between the aforementioned mammalian species and brain regions. SDS-PAGE has shown that the receptor consists of two subunits, alpha (Mr 53000) and beta (Mr 57000) present in equal stoichiometry. A model consistent with the determination of the molecular weight of the native protein, i.e., Mr 230,000, is that of a tetramer alpha 2 beta 2. [3H]Flunitrazepam and [3H]muscimol have been employed as photoaffinity labels to map the benzodiazepine and GABA binding polypeptides respectively. Polyclonal and monoclonal antibodies have been raised to the native bovine GABAA receptor and these have been employed for the further characterisation of the receptor protein.
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PMID:Progress towards the understanding of the GABAA receptor structure. 304 Sep 81

Benzodiazepine receptors were investigated in the cerebral cortex, the hippocampus, the brainstem, and the cerebellum of audiogenic seizure (AGS)-susceptible and seizure-resistant (ER) control rats. In AGS-susceptible rats of Sprague-Dawley descent, muscimol (10-6 M and 3 x 10-5 M) activated the binding of 3H-diazepam (0.4 nM) significantly less than in ER-rats. This finding may be strain selective, since it was not observed in AGS-susceptible rats of Wistar descent. Specific binding of the convulsant benzodiazepine receptor ligand methyl 6,7-dimethoxy-4-ethyl carboline-3-carboxylate (3H-DMCM), the benzodiazepine receptor ligand 3H-diazepam and the chloride channel directed cage convulsant t-butylbicyclophosphorothionate 35S-TBPS were not significantly changed in AGS-susceptible as compared to control rats. Our findings indicate that a disturbance at the level of the benzodiazepine receptor/GABA receptor/chloride channel complex is not a likely general aetiological factor for audigenic seizures in rats.
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PMID:A study on benzodiazepine receptor binding in audiogenic seizure-susceptible rats. 609 92

Majority of adult male albino random-bred mice housed singly or in small groups show agonistic behavior on interaction with a strange male mouse: some of them are predominantly aggressive ('aggressive' mice) while others show defenses or escapes even though their partners are not aggressive ('timid' mice). The remaining males not exhibiting agonistic behavior ('sociable' mice) show more social investigation then aggressive or timid mice and more locomotion then timid mice. Active defensive-escape behavior ('timidity') and inhibition of social investigation and of locomotion is much stronger in an unfamiliar cage with a strange male than in a home cage or on interaction with a female. Effects of 50 drugs on behavior of aggressive and timid male mice on agonistic interactions with non-aggressive male mice in neutral cages were tested. Most of the drugs possessing anxiolytic activity in man reduced active escapes or defenses at doses lower than those inhibiting attacks or locomotion and increased social investigation while most drugs without anxiolytic activity did not show these effects. Some anxiolytic drugs reduced tail-rattling (an ambivalent activity presumably reflecting both attack and escape tendency) at doses lower than those reducing attacks and increased locomotion. Only some benzodiazepines (nitrazepam, oxazepam and diazepam) produced the whole spectrum of these effects indicating a reduced defensive-escape tendency. The present results suggest that a selective inhibition of defensive-escape tendency on agonistic interactions can be a good predictor of anxiolytic activity of drugs. Profiles of effects of seven benzodiazepines in the present model of agonistic interaction to some extent differed: triazolam, clonazepam and flunitrazepam were more sedating (reduced timidity only at doses inhibiting locomotion) while nitrazepam, oxazepam, diazepam and chlordiazepoxide were less sedating (reduced timidity at non-sedative doses, stimulated social investigation and locomotion). Only drugs stimulating GABA-receptor complex (benzodiazepines, barbiturates and GABAergic drugs) inhibited active escapes and defenses at doses lower than those reducing attacks. This suggests that the GABA-receptor complex is involved in regulation of defensive-escape tendency in intraspecies conflict.
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PMID:Can social and agonistic interactions be used to detect anxiolytic activity of drugs? 615 Apr 90

t- Butylbicyclophosphorothionate ( TBPS ), a derivative of potent GABA antagonistic cage convulsants, has recently been introduced ( Squires , R. F., J.E. Casida , M. Richardson, and E. Saederup (1983) Mol. Pharmacol. 13:326-336) as ligand for a GABA-A receptor-linked drug receptor. Using conventionally prepared washed membrane fractions from rat cerebral cortex, we have confirmed that in the presence of 200 mM NaBr [35S] TBPS binds to a high affinity population of binding sites (Kd 26 +/- 5 nM) and that muscimol inhibits [35S] TBPS binding (IC50 0.32 microM) allosterically. In 200 mM NaCl the apparent affinity of [35S] TBPS binding sites is lower (Kd 60 +/- 5 nM), and muscimol has biphasic effects with stimulation at low concentrations of muscimol (EC50 0.023 microM) followed by inhibition at high concentrations (IC50 0.72 microM). Both base line [35S] TBPS binding (in 200 mM NaCl) and muscimol inhibition of [35S] TBPS binding (in 200 mM NaBr) are bidirectionally modulated by the occupancy of benzodiazepine receptors with its ligands. Benzodiazepine receptor agonists, regardless of their structure, enhance and inverse benzodiazepine receptor agonists inhibit base line [35S] TBPS binding and muscimol inhibition of [35S] TBPS binding. Fourteen ligands for benzodiazepine receptors display a similar in vitro profile as benzodiazepine receptor agonists or inverse benzodiazepine receptor agonists on [35S] TBPS binding as their anti- or proconvulsive effects in vivo suggest (Jensen, L. H., E. N. Petersen, and C. Braestrup (1983) Life Sci. 33: 393-399). That [35S] TBPS binding sites are constituents of a GABA benzodiazepine receptor complex is also suggested by a number of membrane pretreatments.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[35S]-t-butylbicyclophosphorothionate binding sites are constituents of the gamma-aminobutyric acid benzodiazepine receptor complex. 632 34

Binding activity for the cage convulsant [35S]-tert- butylbicyclophosphorothionate , which appears to label a site closely associated with the chloride ionophore of the GABAA /benzodiazepine receptor complex has been solubilized from rat cerebral cortex using the zwitterionic detergent CHAPS . Of several detergents screened, only CHAPS and CHAPSO were capable of solubilizing the binding activity with good recovery. The pharmacologic specificity of soluble [35S]-tert- butylbicyclophosphorothionate binding is very similar to the membrane state. In both the membrane and soluble state, [35S]-tert- butylbicyclophosphorothionate binding is enhanced by anions which support inhibitory post-synaptic potentials (" Eccles anions"), suggesting that [35S]-t- butylbicyclophosphorothionate may label chloride channels though to be involved in these potentials. Since this solubilization procedure also preserves GABA and benzodiazepine binding and their regulation by drugs such as barbiturates, purification and isolation of the macromolecular complex including chloride channel and GABA-benzodiazepine sites may be feasible.
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PMID:Solubilization and anionic regulation of cerebral sedative/convulsant receptors labeled with [35S] tert-butylbicyclophosphorothionate (TBPS). 632 79

[35S]t-Butylbicyclophosphorothionate (TBPT), a cage convulsant with picrotoxinin-like activity, binds to rat brain membranes to a single site with an apparent KD of 25.1 +/- 5.6 nM and a Bmax of 1.40 +/- 0.22 pmol/mg protein. TBPT binding to rat brain membranes was inhibited by a variety of convulsant, depressant, anxiolytic, and anticonvulsant drugs that had previously been shown to inhibit [3H]alpha-dihydropicrotoxinin binding. Depressant drugs such as pentobarbital and the nonbarbiturate (+)etomidate inhibited TBPT binding in an uncompetitive manner. Thus, pentobarbital and (+)etomidate decreased both the affinity and the number of binding sites of TBPT to whole brain membranes. The IC50 values of (+)etomidate (9 microM) and pentobarbital (90 microM) are similar to the EC50 values at which they enhance both [3H]gamma-aminobutyric acid and [3H]diazepam binding in cerebral cortex membranes. RO5-4864, which has recently been shown to be a convulsant, also inhibited TBPT binding (IC50 = 10 microM). These results suggest that TBPT binds to the picrotoxinin site and further supports the notion that the picrotoxinin site is an important modulatory site at the benzodiazepine-GABA receptor-ionophore complex.
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PMID:Binding characteristics and interactions of depressant drugs with [35S]t-butylbicyclophosphorothionate, a ligand that binds to the picrotoxinin site. 668 88

Baclofen, the parachlorophenyl analog of GABA, was found to induce catalepsy and to inhibit the traction response in mice. However, baclofen pretreatment, instead of antagonizing methamphetamine stereotypy and apomorphine-induced cage climbing behavior, was found to potentiate these behaviors, thereby ruling out the possibility of its possessing postsynaptic dopamine (DA) receptor blocking activity. The possible mechanism involved in the induction of catalepsy and in the inhibition of the traction response by baclofen is discussed on the basis that baclofen, by inhibiting the firing of the nigrostriatal and mesolimbic DA neurons, reduces the release of DA and thereby produces a functional lack of DA at postsynaptic DA receptor sites with resultant induction of catalepsy and inhibition of the traction response. Further, the hyper-responsiveness to methamphetamine and apomorphine is explained on the basis that, as the postsynaptic DA receptors are acutely deprived of their transmitter, following baclofen pretreatment, they become supersensitive to the DA agonists.
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PMID:Effects of baclofen on dopamine-dependent behaviors in mice. 680 87

Effect of GABA on the motor activity of rats of the first month of life was studied in conditions of free behaviour in the maternal cage. It has been found that at the age of 1-10 days the injection of GABA increases, and at the age of 11-30 days decreases both the general motor activity and the grooming activity. It is suggested that a possible mechanism of the observed effect of GABA consists in the deepening of presynaptic inhibition, which results, during the earlier stages of postnatal ontogeny, in intensifying the autorhythmical activity of spinal motor centres, whereas during the later stages, when the autorhythmical activity of the spinal cord is replaced by reflex excitatory mechanisms, in depressing the latter.
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PMID:[Effect of GABA on motor activity in the rat during the early postnatal period]. 706 53

Although isolated rat pups emit ultrasonic vocalizations (USVs), those kept warm and undisturbed in the home cage with their littermates seldom do. Drugs were administered to 10-day-old pups in the home cage to determine whether pharmacological agents can elicit USV in this familiar environment. Ten-day-old Wistar rats were injected with U50,488, a highly selective kappa opioid agonist; pentylenetetrazol (PTZ), an anxiogenic drug that binds at the GABA-benzodiazepine receptor complex; or naltrexone (NLX), an opiate receptor blocker, and then were returned to their littermates in the home cage. U50,488 increased USV and activity levels, lowered body temperature, and disrupted contact with littermates. PTZ raised activity levels but had a smaller effect on vocalization rates and did not alter temperature or contact with littermates. Behavioral measures and body temperature were unchanged by NLX.
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PMID:Ultrasonic vocalizations are elicited from rat pups in the home cage by pentylenetetrazol and U50,488, but not naltrexone. 828 Mar 94


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