Disease relevance of GABBR1

• BACKGROUND: Polymorphism G1465A in the GABBR1 gene has been suggested as a risk factor for non-lesional temporal lobe epilepsy (TLE); however, this genetic association study has not been independently replicated [1].
• The GABBR1 locus and the G1465A variant is not associated with temporal lobe epilepsy preceded by febrile seizures [1].
• The mapping of the GABABR1 gene to human chromosome 6p21.3, in the vicinity of a susceptibility locus (EJM1) for idiopathic generalized epilepsies, identifies a candidate gene for inherited forms of epilepsy [2].
• To investigate the mechanism of the GABAB-R1/GABAB-R2 interaction and to assess the subunit stoichiometry of the complex, recombinant polypeptide chain fragments containing the heteromerization site were produced by heterologous gene expression in Escherichia coli [3].
• Neurophysiological and pharmacological studies suggest a major role of the GABAB receptor in the epileptogenesis of absence seizures [4].

Psychiatry related information on GABBR1

• Evidence for the gamma-amino-butyric acid type B receptor 1 (GABBR1) gene as a susceptibility factor in obsessive-compulsive disorder [5].
• Its function and location in a susceptibility region for schizophrenia, epilepsy, and dyslexia make GABBR1 a candidate gene for neurobehavioral disorders [6].
• It is increasingly clear that new information on GABAB receptor molecular structure will provide a plethora of targets for pharmaceutical intervention in areas such as drug addiction, nociception and absence seizures [7].
• It was concluded that a GABAB receptor activation due to an endogenous release of GABA caused a depression of the burst activity with a maintained well-coordinated locomotor activity [8].
• This investigation encourages the search for drugs acting on the affective psychopathology of GABAB receptor ligands [9].

High impact information on GABBR1

• We found therapeutic intervention with phenobarbital or phenytoin ineffective, whereas intervention with vigabatrin or the GABAB receptor antagonist CGP 35348 (ref. 2) prevented tonic-clonic convulsions and significantly enhanced survival of the mutant mice [10].
• Here we report the cloning of a complementary DNA encoding a new subtype of the GABAB receptor (GABA(B)R2), which we identified by mining expressed-sequence-tag databases [11].
• 2-OH Saclofen, a GABAB receptor antagonist, prevented the reduction of inhibition, the increase of excitation, and the induction of LTP [12].
• GABAB receptor modulation of synaptic plasticity occurs at frequencies in the range of the endogenous hippocampal theta rhythm, which has been shown to modulate LTP in vivo [12].
• Electrophysiology of GABAA and GABAB receptor subtypes [13].

Chemical compound and disease context of GABBR1

• Baclofen (a selective GABAB receptor agonist) reversibly inhibited synaptic transmission via a presynaptic, pertussis toxin-sensitive mechanism; CGP 35348 (a selective GABAB receptor antagonist) blocked the actions of baclofen [14].
• The inhibitory effect of GABA on cAMP levels was mimicked by the GABAB receptor agonist baclofen (100 microM) and totally abolished by a 4-h pretreatment with pertussis toxin (0.1 microgram/ml) [15].
• We investigated the neuroprotective effects of vinconate (a vinca alkaloid derivative), baclofen (a GABAB receptor agonist), or pentobarbital (a GABAA receptor-effector) on neuronal damage following repeated brief cerebral ischemia in the gerbils [16].

Biological context of GABBR1

• To investigate whether or not the GABBR1 gene is a susceptibility gene for CAE in the Chinese Han population, we systematically screened all the 22 exons and nearby intron regions of the gene and found 12 single nucleotide polymorphisms (SNPs) [17].
• Furthermore the GABA type B receptor 1 (GABBR1) gene has been localized to chromosome 6p21.3 region, which has shown linkage to OCD [5].
• PURPOSE: Recently a coding nonsynonymous single-nucleotide polymorphism (SNP; G1465A) in the GABBR1 gene was reported to be associated with the incidence and severity of temporal lobe epilepsy (TLE) [18].
• We identified critical amino acids delineating a Ca(2+) binding pocket predicted to be adjacent to, but distinct from, a cavity reminiscent of the binding site described for amino acids in mGluRs, GABA-B receptor, and GPRC6a [19].
• Phosphorylation and chronic agonist treatment atypically modulate GABAB receptor cell surface stability [20].

Anatomical context of GABBR1

• The human GABA(B) receptor (GABBR1) maps to the human leukocyte antigen (HLA) region of chromosome 6 [6].
• Gamma-hydroxybutyrate reduces mitogen-activated protein kinase phosphorylation via GABA B receptor activation in mouse frontal cortex and hippocampus [21].
• In COS-7 cells coexpressing gb1a and gb2 receptors, co-immunoprecipitation of gb1a and gb2 receptors was demonstrated, indicating that gb1a and gb2 act as subunits in the formation of a functional GABAB receptor [22].
• GABABR2 is localized to the cell surface in transfected COS cells, and negatively couples to adenylyl cyclase in response to GABA, baclofen, and 3-aminopropyl(methyl)phosphinic acid in CHO cells lacking GABABR1 [23].
• Comparative cellular distribution of GABAA and GABAB receptors in the human basal ganglia: immunohistochemical colocalization of the alpha 1 subunit of the GABAA receptor, and the GABABR1 and GABABR2 receptor subunits [24].

Associations of GABBR1 with chemical compounds

• Baclofen action is inhibited by the GABABR antagonist, 2-hydroxysaclofen [23].
• The effect of a maximally effective concentration of FF (30%, vol/vol) was significantly suppressed by bicuculline, a GABAA receptor antagonist, and saclofen, a GABAB receptor antagonist, added concomitantly [25].
• It has recently been demonstrated that GABABR indeed modulates alpha amino-3-hydroxy-5-methyl-4-isoxalone propionate-type ionotropic glutamate receptor (AMPAR)-mediated and type-1 metabotropic glutamate receptor (mGluR1)-mediated signaling [26].
• Importantly, GABABR2 receptors can form a heteromeric assembly with GABABR1 proteins to operate as a heterodimer that displays robust coupling to inward-rectifying K+ channels, as well as inhibition of forskolin-stimulated adenylate cyclase activity [7].
• On the other hand, application of 500 microM muscimol or 1 mM baclofen, GABAA and GABAB receptor agonists, respectively, were completely without effect [27].

Physical interactions of GABBR1

• Here we examined whether such a mechanism is involved in the quality control of the heterodimeric G protein-coupled GABAB receptor [28].

Other interactions of GABBR1

• DNA sequencing of coding regions and exon/intron boundaries of two candidate genes (POU5F1, GABBR1) in this interval did not reveal disease causing mutations [29].
• The gene encoding GABBR1 is not associated with childhood absence epilepsy in the Chinese Han population [17].
• The gene encoding the human GABABR1 receptor (GABABR1) has recently been mapped to human chromosome 6p21.3 by in situ hybridization, a region that harbors a susceptibility locus (EJM1) for idiopathic generalized epilepsy (IGE) [4].
• In contrast, isolated GABAB-R1 peptides folded into relatively unstable homodimers, whereas GABAB-R2 peptides were largely unstructured [3].
• The GABAB receptor has been mapped to human chromosome 6p21.3 within the HLA class I region close to the HLA-F gene [30].

Analytical, diagnostic and therapeutic context of GABBR1

• Molecular cloning of human GABABR1 and its tissue distribution [31].
• Moreover, animal models suggest that the GABAB receptor plays a critical role in the epileptogenesis of absence seizures [32].
• As administration of GHB, a GABAB receptor agonist and a natural opioid peptide all elicit similar abnormal EEG phenomena, it may be suggested that they are acting via a common pathway [33].
• Western blot analysis reveals widespread expression of the GABABR1 receptor proteins in rat brain with the highest level of expression at early postnatal stages [34].
• Repeated administration of the GABAB receptor agonist CGP44532 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine-seeking in rats [35].

References