Biochemical identification of pharmacologically and functionally distinct GABA receptors in rat brain

Browner, Michelle F.; Ferkany, J.W.; Enna, S.J.

doi:10.1523/jneurosci.01-05-00514.1981

Cited by 98 publications

(30 citation statements)

References 12 publications

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“…The evidence does not exclude that the two sites could be separable in appropriate conditions. Preferential extraction of BZ sites in some conditions has been suggested (Chiu and Rosenberg, 19796;Massotti et al, 1981), but this does not establish that the membrane complex as studied here was dissociated, since there are severalfold more muscimol-binding sites than BZ sites in the brain membranes, and the effects of a detergent on the other classes of those sites may differ palacios et al, 1979;Gavish and Snyder, 1981;Browner et al, 1981; and the present work (Table l)]. Likewise, selective inactivation in particular conditons of one of the two linked sites studied here might occur without their physical separation.…”

Section: Discussionmentioning

confidence: 75%

“…[3H]Muscimol was used here as the probe for the GABAA receptor sites (Hill and Bowery, 1981), in the absence of Na+, so that GABA uptake system or additional classes of GABA-binding sites are not measured (Beaumont et al, 1978;Wang et al, 1979;Browner et al, 1981). Without the extraction in 0.05% Triton medium, the Scatchard plot revealed both a high-and a lower affinity site for [3H]muscimol, but only one class of site (considering the concentration range up to 100 nM [3H]muscimol) after that extraction (Fig.…”

Section: Determination Of Molecular Size Of Receptors In the Membranementioning

confidence: 99%

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The Benzodiazepine/GABA Receptor Complex: Molecular Size in Brain Synaptic Membranes and in Solution

Chang

Barnard

1982

Journal of Neurochemistry

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The molecular size of the benzodiazepine (BZ) receptor in the synaptic membrane of brain cortex (bovine or rat) was determined by an improved version of the radiation inactivation method to be 220,000. An identical size was found simultaneously for the associated gamma-aminobutyric acid (GABA) receptor and for the component binding beta-carboline esters. It is proposed that all three activities reside in a single protein or protein complex in the membrane. The size in solution, after extraction into Triton X-100 medium from exhaustively washed membranes, was estimated by sedimentation constant (9.4S) and by gel filtration ( approximately 230,000 apparent MW), again with the BZ and GABA binding activities behaving identically. This size applies to the component that undergoes photoaffinity labelling by [3H]flunitrazepam in the membrane, and contains a 51,000 Mr polypeptide as the BZ-binding subunit. It is concluded that a protein complex or oligomer of 200,000-220,000 MW carries a class of BZ-binding sites and an associated class of GABAA sites.

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Section: Discussionmentioning

confidence: 75%

Section: Determination Of Molecular Size Of Receptors In the Membranementioning

confidence: 99%

The Benzodiazepine/GABA Receptor Complex: Molecular Size in Brain Synaptic Membranes and in Solution

Chang

Barnard

1982

Journal of Neurochemistry

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“…Biochemically, low- and high-affinity binding sites can be selectively and independently interconversed by chaotropic agents or chemicals modifying histidine or tyrosine residues (Browner et al, 1981; Burch et al, 1983; Maksay and Ticku, 1984). Presently, it is not known whether the sites recognized by [ 3 H]muscimol in brain sections could be transformed to low-affinity binding sites.…”

Section: Discussionmentioning

confidence: 99%

“…Spatial distribution of high-affinity [ 3 H]muscimol binding at low nanomolar concentrations differs from that of benzodiazepine site ligands throughout the rodent brain (Korpi et al, 2002a; Mans et al, 1992; Olsen et al, 1990; Palacios et al, 1981). [ 3 H]Muscimol and [ 3 H]GABA bind to two kinds of agonist binding sites on the GABA A -Rs with three to twenty-fold difference in affinity (Browner et al, 1981; Burch et al, 1983; Wang et al, 1979), with the binding site being formed at α/β interfaces (Sigel and Buhr, 1997). …”

Section: Introductionmentioning

confidence: 99%

Prototypic GABAA Receptor Agonist Muscimol Acts Preferentially Through Forebrain High-Affinity Binding Sites

Chandra

Halonen

Lindén

et al. 2009

Neuropsychopharmacol

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Muscimol has been regarded as a universal agonist for all GABAA receptor subtypes. However, brain regional distribution of muscimol’s high-affinity binding sites greatly differs from those of other binding sites of the GABAA receptor. To test whether behavioral effects of muscimol correlated with the density of high-affinity [3H]muscimol binding, we examined several GABAA receptor subunit gene-modified mouse lines: α1, α4, or δ knockouts (KO), α4+δ double KO, and Thy1.2 promoter-driven α6 transgenic mice (Thy1α6). We determined the high-affinity [3H]muscimol binding in brain sections by quantitative autoradiography and sedative/ataxic effects induced in vivo by muscimol using a constant speed rotarod. α4-KO mice had reduced [3H]muscimol binding in the caudate-putamen, thalamus and hippocampus, and were less sensitive to the behavioral impairment by muscimol. Similarly, δ-KO mice also had reduced binding to forebrain regions and a lower behavioral sensitivity to muscimol than their wild-type controls. In contrast, α1-KO mice had unaltered behavioral sensitivity to muscimol and unaltered [3H]muscimol binding, even though previous studies have demonstrated dramatically reduced binding to various other GABAA receptor sites in these mice. Finally, Thy1α6 mice exhibited increased behavioral sensitivity to muscimol, and to another direct GABA-site agonist gaboxadol, and increased [3H]muscimol binding in the cerebral cortex and hippocampus. Thus, the differences in sedative and motor-impairing actions of muscimol in various mouse models correlated with the level of forebrain high-affinity [3H]muscimol binding. These data suggest that a small special population of GABAA receptors, most likely extrasynaptic non-α1 containing receptors, strongly contributes to the in vivo pharmacological effects of muscimol.

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“…This is sup ported by the similarity of the pattern obtained in our experiments compared with earlier auto radio graphic studies (McCabe and Wamsley, 1986;Bow ery et aI., 1987). The BZDs bind only to the low- affinity form (Costa et al, 1979;Browner et al, 1981); thus, the regional differences between the binding of the BZDs and muscimol should reflect differences in distribution of the two forms. The binding of TBPS clearly does not correlate with that of the BZD site or GAB A high-affinity site (as reflected by muscimol), when examined on a regional basis.…”

Section: Distribution Of Binding Of Ligandsmentioning

confidence: 99%

Regional Distribution and Kinetics of Three Sites on the GABA_A Receptor: Lack of Effect of Portacaval Shunting

Mans

Kukulka

McAvoy

et al. 1992

J Cereb Blood Flow Metab

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Summary: The regional distribution of binding sites on the GABAA receptor and their kinetic parameters were measured by quantitative autoradiography in brains from normal rats and rats with a portacaval shunt, a model of portal systemic encephalopathy in which GAB A neuro transmission may be altered. The ligands used were eHlflunitrazepam (a benzodiazepine-site agonist), [3H]_ Ro15-1788 (a benzodiazepine-site antagonist), eH]musci mol (a GABA-site agonist), and eSS]t-butylbicyclo phosphorothionate eSS-TBPS, a convulsant that binds to a site near the chloride channel). Some brains were ana lyzed by computerized image analysis and three dimensional reconstruction. The regional distribution of binding of the benzodiazepines was very similar, but the patterns obtained with eH]muscimol and eSS]TBPS were The GABAA receptor is one of two types of re ceptor that mediate inhibitory GABA neuro transmission throughout the brain. This receptor is a complex oligomeric protein that forms a Cl-ion ophore that is the active component of the receptor.(The other major type of GABA receptor, the GABAB receptor, is not associated with a Cl channel, and is not considered here.) The GABAA receptor is found as a low-affinity and a high affinity type (binding GAB A with mM and nM af finity, respectively). The low-affinity type has a site for benzodiazepine (BZD) binding (Costa et aI. , 1979; Browner et aI. , 1981), and is believed to be the functionally active form (Tallman and Gallagher, For each ligand, the Kd showed a significant heterogene ity among brain regions (at least threefold), contrary to conclusions drawn from earlier studies. In portacaval shunted rats, binding of all four ligands was essentially unchanged from that in control rats, indicating that, if there was an abnormality in GABA neurotransmission during portal systemic shunting, it was not reflected by altered binding to the main sites on the GABAA receptor.

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Biochemical identification of pharmacologically and functionally distinct GABA receptors in rat brain

Cited by 98 publications

References 12 publications

The Benzodiazepine/GABA Receptor Complex: Molecular Size in Brain Synaptic Membranes and in Solution

The Benzodiazepine/GABA Receptor Complex: Molecular Size in Brain Synaptic Membranes and in Solution

Prototypic GABAA Receptor Agonist Muscimol Acts Preferentially Through Forebrain High-Affinity Binding Sites

Regional Distribution and Kinetics of Three Sites on the GABA_A Receptor: Lack of Effect of Portacaval Shunting

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Biochemical identification of pharmacologically and functionally distinct GABA receptors in rat brain

Cited by 98 publications

References 12 publications

The Benzodiazepine/GABA Receptor Complex: Molecular Size in Brain Synaptic Membranes and in Solution

The Benzodiazepine/GABA Receptor Complex: Molecular Size in Brain Synaptic Membranes and in Solution

Prototypic GABAA Receptor Agonist Muscimol Acts Preferentially Through Forebrain High-Affinity Binding Sites

Regional Distribution and Kinetics of Three Sites on the GABAA Receptor: Lack of Effect of Portacaval Shunting

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Regional Distribution and Kinetics of Three Sites on the GABA_A Receptor: Lack of Effect of Portacaval Shunting