Disease relevance of Gabrb2

• Allelic variation in the GABA A receptor gamma2 subunit is associated with genetic susceptibility to ethanol-induced motor incoordination and hypothermia, conditioned taste aversion, and withdrawal in BXD/Ty recombinant inbred mice [1].
• Partial restoration of striatal GABAA receptor balance by functional mesencephalic dopaminergic grafts in mice with hereditary parkinsonism [2].
• Aberrant expression of GABAA receptor subunits in the tottering mouse: an animal model for absence seizures [3].
• Neurons derived from embryonal carcinoma (P19) cells express multiple GABAA receptor subunits and fully functional GABAA receptors [4].
• The gamma-aminobutyric acid A (GABA-A) receptor mediates inhibitory neurotransmission in the brain and as such may be involved in certain neurological movement disorders, such as tremor [5].

Psychiatry related information on Gabrb2

• This model implicates GABAA-receptor dysfunction in patients as a causal predisposition to anxiety disorders [6].
• Patients with panic disorders show a deficit of GABAA receptors in the hippocampus, parahippocampus and orbitofrontal cortex [6].
• Maternal behavior regulates benzodiazepine/GABAA receptor subunit expression in brain regions associated with fear in BALB/c and C57BL/6 mice [7].
• Electroconvulsive shock alters GABAA receptor subunit mRNAs: use of quantitative PCR methodology [8].
• Thus, genes coding for the GABAA receptor or associated proteins may be critical determinants of individual differences in ethanol sensitivity [9].

High impact information on Gabrb2

• PrP null mice show abnormalities of synaptic neurophysiology, in particular weakened GABAA receptor-mediated fast inhibition and impaired long-term potentiation in the hippocampus [10].
• Here we show that this tonic conductance is absent in granule cells that lack the alpha6 and delta-subunits of the GABAA receptor [11].
• In cerebellar granule cells, although the frequency of inhibitory synaptic currents is relatively low, the spillover of synaptically released GABA (gamma-aminobutyric acid) gives rise to a persistent conductance mediated by the GABA A receptor that also modifies the excitability of granule cells [11].
• In nicotinic acetylcholine receptors (nAChR), as well as glycine, GABAA (gamma-aminobutyric acid), serotonin (5-HT3), and GluCl glutamate receptors, a leucine residue at the approximate midpoint of the M2 transmembrane domain (the 9' position) is conserved across most known subunits [12].
• These findings indicate that the anxiolytic effect of benzodiazepine drugs is mediated by alpha2 GABAA receptors, which are largely expressed in the limbic system, but not by alpha3 GABAA receptors, which predominate in the reticular activating system [13].

Chemical compound and disease context of Gabrb2

• Benzodiazepine- and alcohol-induced ataxias in rodents have been proposed to be affected by the gamma-aminobutyric acid type A (GABAA) receptor alpha 6 subunit, which contributes to receptors specifically expressed in cerebellar granule cells [14].
• The expression of the gamma 2 subunit into functional GABAA receptors has been examined in the embryonal carcinoma (EC) cell line P19, a pluripotent cell line which differentiates into a neuronal phenotype after exposure to retinoic acid [15].
• Since the diazepam-induced increase of [3H]muscimol binding is paralleled by a significant potentiation of the inhibitory effect of muscimol on locomotor activity, it is proposed that the facilitatory action on GABAergic transmission elicited in vivo by diazepam is mediated by an increase in the Bmax of the binding sites of GABAA receptors [16].
• Status epilepticus in mice deficient for succinate semialdehyde dehydrogenase: GABAA receptor-mediated mechanisms [17].
• Involvement of glycine and GABAA receptors in the pathogenesis of spinal myoclonus: in vitro studies in the isolated neonatal rodent spinal cord [18].

Biological context of Gabrb2

• Our results indicate that, in cerebellar neurons, the expression of specific GABAA/BZ receptor subunit mRNAs, polypeptides, and binding sites is independently regulated by in vivo administration of alcohol [19].
• METHODS: The effect of etomidate and propofol on core body temperature were measured using radiotelemetry in freely moving GABAA receptor beta 2N265S mutant mice and wild-type controls [20].
• These results further demonstrate clustering of the GABAA receptor subunit genes on mouse chromosomes and the synteny for these clusters between the mouse and human genomes [21].
• Functional modulation of GABAA receptors by cAMP-dependent protein phosphorylation [22].
• gamma-Aminobutyric acidA (GABAA) receptors are ligand-gated ion channels that mediate inhibitory synaptic transmission in the central nervous system [22].

Anatomical context of Gabrb2

• Synaptic vesicle proteins, AMPA- and NMDA-type glutamate receptors, GABAA receptors, and the putative synapse-organizing proteins PSD-95, GKAP, and gephyrin formed numerous clusters at synaptic sites [23].
• Enhancement of the activation of GABAA receptors is a common feature of many sedative and hypnotic drugs, and it is probable that the GABAA receptor complex is a molecular target for these drugs in the mammalian central nervous system [24].
• Synaptic clustering of GABAA receptors in mice heterozygous for the gamma2 subunit was reduced, mainly in hippocampus and cerebral cortex [6].
• The role of phosphorylation in receptor function was studied using recombinant receptors expressed in kidney cells and Xenopus oocytes and was compared with native neuronal GABAA receptors [25].
• GABAA receptor {alpha}4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol [26].

Associations of Gabrb2 with chemical compounds

• The mammalian GABAA/benzodiazepine (GABAA/BZ) receptor is comprised of several subunit isoforms: alpha 1-6, beta 1-13, gamma 1-3 and delta [27].
• Deletion of either the alpha1 or beta2 subunits reduced the muscimol-stimulated 36Cl36 influx in cortical microsacs suggesting that these mutant mice have reduced number of functional brain GABAA receptors [24].
• BACKGROUND: The authors have previously described that the gamma-aminobutyric acid type A (GABAA) receptor beta 2N265S mutation results in a knock-in mouse with reduced sensitivity to etomidate [20].
• Both alpha1 (-/-) and beta2 (-/-) null mutant mice showed markedly decreased sleep time induced by nonselective benzodiazepine, flurazepam, and GABAA agonist, 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol [24].
• The gamma-aminobutyric acid type A (GABAA) receptor gamma 2-subunit is important for benzodiazepine action [28].

Physical interactions of Gabrb2

• The gamma 2 subunit and gephyrin are thus interdependent components of the same synaptic complex that is critical for postsynaptic clustering of abundant subtypes of GABAA receptors in vivo [29].
• To further study the putative gamma-butyrolactone site of the GABAA/chloride channel complex, constrained derivatives of convulsant and anticonvulsant alpha,alpha-disubstituted gamma-butyrolactones (alpha-spirocyclopropyl- and alpha-spirocyclopentyl-gamma-butyrolactones) were synthesized and evaluated biologically [30].
• Using the selective GABAA receptor agonist isoguvacine it could be demonstrated that the GABAB receptors are functionally coupled to GABAA receptors in the neurons leading to a disinhibitory action of GABAB receptor agonists [31].
• It is therefore concluded that whilst chlormethiazole effectively antagonises the convulsive behavioural syndrome induced by injection of NMDLA, it does not do so by interacting with the NMDA receptor complex but more probably by its known interaction with the GABAA receptor complex [32].
• Diazepam binding inhibitor (DBI) is a putative endogenous ligand capable of binding to the central type benzodiazepine (BZD) receptor located on the GABAA receptor and the peripheral type BZD receptor on the mitochondrial outer membrane [33].

Co-localisations of Gabrb2

• Likewise, the distribution, number and size of GABAA receptor clusters colocalized with gephyrin are similar to wild-type in both juvenile and adult mice [34].
• Here, we show by double-immunofluorescence staining that dystrophin is extensively colocalized with GABAA receptor subunit clusters in these brain regions [35].

Regulatory relationships of Gabrb2

• Cerebellar granule-cell-specific GABAA receptors attenuate benzodiazepine-induced ataxia: evidence from alpha 6-subunit-deficient mice [14].
• Although the BDNF-induced GABAA receptor internalization was sensitive to K252a, it did not become manifest until 5 min after exposure to BDNF [36].
• A recent in vitro study [Ganguly et al. (2001) Cell, 105, 521-532] showed that KCC2 expression may be under the trophic control of GABAA receptor-mediated transmission [37].
• We hypothesized that Hcy transduces MVEC remodeling by increasing metalloproteinase activity and shedding beta-1 integrin by inactivating the GABA-A/B receptors, thus behaving as an excitatory neurotransmitter [38].
• The inhibitory effects of GABA on glucagon secretion by alpha TC6 cells were blocked by the GABAA receptor antagonist bicuculline and were dissociated from the inhibitory effects of glucose [39].

Other interactions of Gabrb2

• Differential cell surface expression of GABAA receptor alpha1, alpha6, beta2 and beta3 subunits in cultured mouse cerebellar granule cells influence of cAMP-activated signalling [40].
• We compare the sequence and expression of the beta 1, beta 2 and beta 3 subunits of GABAA receptors in two inbred strains of mice, DBA/2J and C57BL/6J, which differ markedly in seizure susceptibility and in a variety of behaviors related to alcohol [41].
• This showed that although Sts may cause alterations in GABAA subunit expression, these changes do not result in increased fear reactivity [42].
• GABAA, GABAC, and NMDA receptor subunit expression in the suprachiasmatic nucleus and other brain regions [43].
• Thus, we have identified an abnormality in the GABAA receptor profile of stg/stg mutant mice that might underpin its irregular phenotype [44].

Analytical, diagnostic and therapeutic context of Gabrb2

• In the present study, [35S]cRNA probes were used to examine the appearance and distribution of GABAA/BZ beta 1, beta 2, and beta 3 subunit mRNAs in the developing C57BL/6 mouse cerebellum by in situ hybridization [45].
• In primary embryonic rat neuronal cell cultures, a similar regulation of GABAA receptors by PKA was observed [22].
• Site-specific mutagenesis of the serine residue phosphorylated by PKA completely eliminated the PKA phosphorylation and modulation of the GABAA receptor [22].
• Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics [46].
• GABAA receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity, and memory functions, and the enhancement of GABAA receptor-mediated fast synaptic inhibition is the basis for the pharmacotherapy of various neurological and psychiatric disorders [46].

References