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  • Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. 15788779

    The proinflammatory cytokine tumor necrosis factor-alpha (TNFalpha) causes a rapid exocytosis of AMPA receptors in hippocampal pyramidal cells and is constitutively required for the maintenance of normal surface expression of AMPA receptors. Here we demonstrate that TNFalpha acts on neuronal TNFR1 receptors to preferentially exocytose glutamate receptor 2-lacking AMPA receptors through a phosphatidylinositol 3 kinase-dependent process. This increases excitatory synaptic strength while changing the molecular stoichiometry of synaptic AMPA receptors. Conversely, TNFalpha causes an endocytosis of GABA(A) receptors, resulting in fewer surface GABA(A) receptors and a decrease in inhibitory synaptic strength. These results suggest that TNFalpha can regulate neuronal circuit homeostasis in a manner that may exacerbate excitotoxic damage resulting from neuronal insults.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Polycomblike protein PHF1b: a transcriptional sensor for GABA receptor activity. 23879974

    The γ-aminobutyric acid (GABA) type A receptor (GABA(A)R) contains the recognition sites for a variety of agents used in the treatment of brain disorders, including anxiety and epilepsy. A better understanding of how receptor expression is regulated in individual neurons may provide novel opportunities for therapeutic intervention. Towards this goal we have studied transcription of a GABA(A)R subunit gene (GABRB1) whose activity is autologously regulated by GABA via a 10 base pair initiator-like element (β(1)-INR).By screening a human cDNA brain library with a yeast one-hybrid assay, the Polycomblike (PCL) gene product PHD finger protein transcript b (PHF1b) was identified as a β(1)-INR associated protein. Promoter/reporter assays in primary rat cortical cells demonstrate that PHF1b is an activator at GABRB1, and chromatin immunoprecipitation assays reveal that presence of PHF1 at endogenous Gabrb1 is regulated by GABA(A)R activation.PCL is a member of the Polycomb group required for correct spatial expression of homeotic genes in Drosophila. We now show that PHF1b recognition of β(1)-INR is dependent on a plant homeodomain, an adjacent helix-loop-helix, and short glycine rich motif. In neurons, it co-immunoprecipitates with SUZ12, a key component of the Polycomb Repressive Complex 2 (PRC2) that regulates a number of important cellular processes, including gene silencing via histone H3 lysine 27 trimethylation (H3K27me3).The observation that chronic exposure to GABA reduces PHF1 binding and H3K27 monomethylation, which is associated with transcriptional activation, strongly suggests that PHF1b may be a molecular transducer of GABA(A)R function and thus GABA-mediated neurotransmission in the central nervous system.
    Document Type:
    Reference
    Product Catalog Number:
    07-448
    Product Catalog Name:
    Anti-monomethyl-Histone H3 (Lys27) Antibody

  • Coactivation of GABA receptors inhibits the JNK3 apoptotic pathway via disassembly of GluR6-PSD-95-MLK3 signaling module in KA-induced seizure. 19694794

    Past work has demonstrated that kainic acid (KA)-induced seizures could cause the enhancement of excitation and lead to neuronal death in rat hippocampus. To counteract such an imbalance between excitation and inhibition, we designed experiments by activating the inhibitory gamma-aminobutyric acid (GABA) receptor to investigate whether such activation suppresses the excitatory glutamate signaling induced by KA and to elucidate the underlying molecular mechanisms.
    Document Type:
    Reference
    Product Catalog Number:
    S7100
    Product Catalog Name:
    ApopTag® Peroxidase In Situ Apoptosis Detection Kit

  • Prevalence of the GABAA receptor assemblies containing alpha1-subunit in the rat cerebellum and cerebral cortex as determined by immunoprecipitation: lack of modulation b ... 10101248

    The anti-alpha1 antibody elicited higher immunoprecipitation (%) values of the [3H]flunitrazepam and [3H]muscimol binding activity in the rat cerebellum vs. cerebral cortex, whereas immunoprecipitation values for [3H]Ro 15-4513 and [3H]zolpidem were comparable in these brain regions. Chronic ethanol administration neither changed the radioligand binding to the immunoprecipitated pellet nor the percentage immunoprecip-itation values, thereby indicating that chronic ethanol did not result in down-regulation of the GABAA receptor assemblies containing alpha1-subunit.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • GABAA receptor activity shapes the formation of inhibitory synapses between developing medium spiny neurons. 26300728

    Basal ganglia play an essential role in motor coordination and cognitive functions. The GABAergic medium spiny neurons (MSNs) account for ~95% of all the neurons in this brain region. Central to the normal functioning of MSNs is integration of synaptic activity arriving from the glutamatergic corticostriatal and thalamostriatal afferents, with synaptic inhibition mediated by local interneurons and MSN axon collaterals. In this study we have investigated how the specific types of GABAergic synapses between the MSNs develop over time, and how the activity of GABAA receptors (GABAARs) influences this development. Isolated embryonic (E17) MSNs form a homogenous population in vitro and display spontaneous synaptic activity and functional properties similar to their in vivo counterparts. In dual whole-cell recordings of synaptically connected pairs of MSNs, action potential (AP)-activated synaptic events were detected between 7 and 14 days in vitro (DIV), which coincided with the shift in GABAAR operation from depolarization to hyperpolarization, as detected indirectly by intracellular calcium imaging. In parallel, the predominant subtypes of inhibitory synapses, which innervate dendrites of MSNs and contain GABAAR α1 or α2 subunits, underwent distinct changes in the size of postsynaptic clusters, with α1 becoming smaller and α2 larger over time, while both the percentage and the size of mixed α1/α2-postsynaptic clusters were increased. When activity of GABAARs was under chronic blockade between 4-7 DIV, the structural properties of these synapses remained unchanged. In contrast, chronic inhibition of GABAARs between 7-14 DIV led to reduction in size of α1- and α1/α2-postsynaptic clusters and a concomitant increase in number and size of α2-postsynaptic clusters. Thus, the main subtypes of GABAergic synapses formed by MSNs are regulated by GABAAR activity, but in opposite directions, and thus appear to be driven by different molecular mechanisms.
    Document Type:
    Reference
    Product Catalog Number:
    MAB341
    Product Catalog Name:
    Anti-GABA A Receptor β 2,3 Chain Antibody, clone BD17

  • Activation of GABA receptors attenuates neuronal apoptosis through inhibiting the tyrosine phosphorylation of NR2A by Src after cerebral ischemia and reperfusion. 18022328

    Cerebral ischemia can induce both the increase of excitation and the decrease of inhibition, which leads to neuronal excitotoxicity. Since glutamatergic and GABAergic transmissions work by each counterbalancing the function of the other, enhancing GABAergic activity should balance excessive glutamatergic excitation. But the potential mechanisms underlying these effects are obscure. Here, we used two GABA agonists, muscimol and baclofen, and performed immunoblotting, immunoprecipitation and histology analysis to evaluate the neuroprotective effects by stimulating GABA receptors in rat four-vessel occlusion (4-VO) ischemic model, and to investigate the potential mechanism. Our results indicate that whether in global cerebral ischemia in vivo, or in oxygen glucose deprivation (OGD) in vitro, coapplication of muscimol with baclofen can protect neurons from neuronal death through down-regulating the function of N-methyl-d-aspartic acid (NMDA) receptors via attenuating the tyrosine phosphorylation of NR2A subunit. We further elucidate that the phosphorylation level of Src kinase and the interaction among Src, post-synaptic density protein 95 and NR2A were also suppressed by coapplication of muscimol with baclofen. Both MK-801, a specific antagonist of NMDA receptors, and chelerythrine, an inhibitor of protein kinase C (PKC), could down-regulate the phosphorylation of NR2A via inhibiting the activation of Src and PKC respectively. These results suggest that the modified pattern of dynamic balance between excitation and inhibition by coactivation of the GABA receptors in cerebral ischemia can attenuate the excitatory NMDAR via inhibiting a novel postsynaptic NMDAR/Src-mediated signal amplification, the 'NMDAR-Ca(2+) --> PKC --> Src --> NMDAR-Ca(2+)' cycle.
    Document Type:
    Reference
    Product Catalog Number:
    05-184

  • Mapping of GABAA receptor alpha 5 and alpha 6 subunit-like immunoreactivity in rat brain. 1331915

    The distribution of the alpha 5 and alpha 6 subunits of the GABAA receptor has been mapped in rat brain using affinity-purified antibodies generated against peptide sequences unique to the respective polypeptides. alpha 5 Subunit-like immunoreactivity was of low density but was distributed across several cell groups including cortical interneurones, hippocampal CA3 pyramidal neurones, the anterior thalamic reticular nucleus and cerebellar Purkinje neurones. alpha 6 Subunit-like immunoreactivity was observed in high density in cerebellar granule cells. These patterns are compatible with in situ hybridisation studies and provide a further anatomical substrate for GABAA receptor heterogeneity in the CNS.
    Document Type:
    Reference
    Product Catalog Number:
    AB5610

  • Altered cortical GABAA receptor composition, physiology, and endocytosis in a mouse model of a human genetic absence epilepsy syndrome. 23744069

    Patients with generalized epilepsy exhibit cerebral cortical disinhibition. Likewise, mutations in the inhibitory ligand-gated ion channels, GABAA receptors (GABAARs), cause generalized epilepsy syndromes in humans. Recently, we demonstrated that heterozygous knock-out (Hetα1KO) of the human epilepsy gene, the GABAAR α1 subunit, produced absence epilepsy in mice. Here, we determined the effects of Hetα1KO on the expression and physiology of GABAARs in the mouse cortex. We found that Hetα1KO caused modest reductions in the total and surface expression of the β2 subunit but did not alter β1 or β3 subunit expression, results consistent with a small reduction of GABAARs. Cortices partially compensated for Hetα1KO by increasing the fraction of residual α1 subunit on the cell surface and by increasing total and surface expression of α3, but not α2, subunits. Co-immunoprecipitation experiments revealed that Hetα1KO increased the fraction of α1 subunits, and decreased the fraction of α3 subunits, that associated in hybrid α1α3βγ receptors. Patch clamp electrophysiology studies showed that Hetα1KO layer VI cortical neurons exhibited reduced inhibitory postsynaptic current peak amplitudes, prolonged current rise and decay times, and altered responses to benzodiazepine agonists. Finally, application of inhibitors of dynamin-mediated endocytosis revealed that Hetα1KO reduced base-line GABAAR endocytosis, an effect that probably contributes to the observed changes in GABAAR expression. These findings demonstrate that Hetα1KO exerts two principle disinhibitory effects on cortical GABAAR-mediated inhibitory neurotransmission: 1) a modest reduction of GABAAR number and 2) a partial compensation with GABAAR isoforms that possess physiological properties different from those of the otherwise predominant α1βγ GABAARs.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Ligand-gated ion channel subunit partnerships: GABAA receptor alpha6 subunit gene inactivation inhibits delta subunit expression. 9006978

    Cerebellar granule cells express six GABAA receptor subunits abundantly (alpha1, alpha6, beta2, beta3, gamma2, and delta) and assemble various pentameric receptor subtypes with unknown subunit compositions; however, the rules guiding receptor subunit assembly are unclear. Here, removal of intact alpha6 protein from cerebellar granule cells allowed perturbations in other subunit levels to be studied. Exon 8 of the mouse alpha6 subunit gene was disrupted by homologous recombination. In alpha6 -/- granule cells, the delta subunit was selectively degraded as seen by immunoprecipitation, immunocytochemistry, and immunoblot analysis with delta subunit-specific antibodies. The delta subunit mRNA was present at wild-type levels in the mutant granule cells, indicating a post-translational loss of the delta subunit. These results provide genetic evidence for a specific association between the alpha6 and delta subunits. Because in alpha6 -/- neurons the remaining alpha1, beta2/3, and gamma2 subunits cannot rescue the delta subunit, certain potential subunit combinations may not be found in wild-type cells.
    Document Type:
    Reference
    Product Catalog Number:
    AB5610