GABAB
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PROVIDER: S-EPMC2884684 | biostudies-literature | 2009 Nov
REPOSITORIES: biostudies-literature
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Project description:GABAB receptors mediate slow synaptic inhibition in the nervous system. In transfected cells, functional GABAB receptors are usually only observed after coexpression of GABAB(1) and GABAB(2) subunits, which established the concept of heteromerization for G-protein-coupled receptors. In the heteromeric receptor, GABAB(1) is responsible for binding of GABA, whereas GABAB(2) is necessary for surface trafficking and G-protein coupling. Consistent with these in vitro observations, the GABAB(1) subunit is also essential for all GABAB signaling in vivo. Mice lacking the GABAB(1) subunit do not exhibit detectable electrophysiological, biochemical, or behavioral responses to GABAB agonists. However, GABAB(1) exhibits a broader cellular expression pattern than GABAB(2), suggesting that GABAB(1) could be functional in the absence of GABAB(2). We now generated GABAB(2)-deficient mice to analyze whether GABAB(1) has the potential to signal without GABAB(2) in neurons. We show that GABAB(2)-/- mice suffer from spontaneous seizures, hyperalgesia, hyperlocomotor activity, and severe memory impairment, analogous to GABAB(1)-/- mice. This clearly demonstrates that the lack of heteromeric GABAB(1,2) receptors underlies these phenotypes. To our surprise and in contrast to GABAB(1)-/- mice, we still detect atypical electrophysiological GABAB responses in hippocampal slices of GABAB(2)-/- mice. Furthermore, in the absence of GABAB(2), the GABAB(1) protein relocates from distal neuronal sites to the soma and proximal dendrites. Our data suggest that association of GABAB(2) with GABAB(1) is essential for receptor localization in distal processes but is not absolutely necessary for signaling. It is therefore possible that functional GABAB receptors exist in neurons that naturally lack GABAB(2) subunits.
| S-EPMC6729668 | biostudies-literature
Project description: Not available
| S-EPMC4215391 | biostudies-literature
Project description:Aim: To gain insight into the pathways by which GABABR activation may influence long-term changes in synaptic plasticity and neuronal growth and morphology we investigated changes in gene expression in cultured hippocampal neurones evoked by the GABABR agonist baclofen. We used cDNA microarray gene expression profiling to identify candidate genes that are differentially expressed in the hippocampal neurones following GABABR activation. Experimental design: The cDNA microarray used in the present study is the NIA Neuroarray containing 1152 genes relevant to neurobiology. NIA Neuroarray probes were hybridised in triplicate with targets derived from control and baclofen-treated neurones. Conclusion: Our novel data on down-stream, late phase consequences of GABABR signalling provide a basis for future studies to investigate these changes in gene expression at the protein, cell biology and functional levels. Furthermore, the changes in gene expression identified will shed light on the multiple roles of GABABRs. Keywords: repeat sample
2005-04-06 | GSE1656 | GEO
Project description:The long-lasting actions of the inhibitory neurotransmitter GABA result from the activation of metabotropic GABA(B) receptors. Enhanced GABA(B)-mediated IPSCs are critical for the generation of generalized thalamocortical seizures. Here, we demonstrate that GABA(B)-mediated IPSCs recorded in the thalamus are primarily defined by GABA diffusion and activation of distal extrasynaptic receptors potentially up to tens of micrometers from synapses. We also show that this diffusion is differentially regulated by two astrocytic GABA transporters, GAT1 and GAT3, which are localized near and far from synapses, respectively. A biologically constrained model of GABA diffusion and uptake shows how the two GATs differentially modulate amplitude and duration of GABA(B) IPSCs. Specifically, the perisynaptic expression of GAT1 enables it to regulate GABA levels near synapses and selectively modulate peak IPSC amplitude, which is primarily dependent on perisynaptic receptor occupancy. GAT3 expression, however, is broader and includes distal extrasynaptic regions. As such, GAT3 acts as a gatekeeper to prevent diffusion of GABA away from synapses toward extrasynaptic regions that contain a potentially enormous pool of GABA(B) receptors. Targeting this gatekeeper function may provide new pharmacotherapeutic opportunities to prevent the excessive GABA(B) receptor activation that appears necessary for thalamic seizure generation.
| S-EPMC3056552 | biostudies-literature
Project description:Metabotropic γ-aminobutyric acid G protein-coupled receptors (GABAB) represent one of the two main types of inhibitory neurotransmitter receptors in the brain. These receptors act both pre- and postsynaptically by modulating the transmission of neuronal signals and are involved in a range of neurological diseases, from alcohol addiction to epilepsy. A series of recent cryo-EM studies revealed critical details of the activation mechanism of GABAB Structures are now available for the receptor bound to ligands with different modes of action, including antagonists, agonists, and positive allosteric modulators, and captured in different conformational states from the inactive apo to the fully active state bound to a G protein. These discoveries provide comprehensive insights into the activation of the GABAB receptor, which not only broaden our understanding of its structure, pharmacology, and physiological effects but also will ultimately facilitate the discovery of new therapeutic drugs and neuromodulators.
| S-EPMC8163086 | biostudies-literature
Project description:ObjectiveSuccinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder of GABA degradation leading to elevations in brain GABA and γ-hydroxybutyric acid (GHB). The effect of chronically elevated GABA and GHB on cortical excitability is unknown. We hypothesized that use-dependent downregulation of GABA receptor expression would promote cortical disinhibition rather than inhibition, predominantly via presynaptic GABAergic mechanisms.MethodsWe quantified the magnitude of excitation and inhibition in primary motor cortex (M1) in patients with SSADH deficiency, their parents (obligate heterozygotes), age-matched healthy young controls, and healthy adults using single and paired pulse transcranial magnetic stimulation (TMS).ResultsLong interval intracortical inhibition was significantly reduced and the cortical silent period was significantly shortened in patients with SSADH deficiency compared to heterozygous parents and control groups.ConclusionsSince long interval intracortical inhibition and cortical silent period are thought to reflect GABA(B) receptor-mediated inhibitory circuits, our results point to a particularly GABA(B)-ergic motor cortex dysfunction in patients with SSADH deficiency. This human phenotype is consistent with the proposed mechanism of use-dependent downregulation of postsynaptic GABA(B) receptors in SSADH deficiency animal models. Additionally, the results suggest autoinhibition of GABAergic neurons. This first demonstration of altered GABA(B)-ergic function in patients with SSADH deficiency may help to explain clinical features of the disease, and suggest pathophysiologic mechanisms in other neurotransmitter-related disorders.
| S-EPMC3385496 | biostudies-literature
Project description:Metabotropic GABAB receptor is a G protein-coupled receptor that mediates inhibitory neurotransmission in the CNS. It functions as an obligatory heterodimer of GABAB receptor 1 (GBR1) and GABAB receptor 2 (GBR2) subunits. The association between GBR1 and GBR2 masks an endoplasmic reticulum (ER) retention signal in the cytoplasmic region of GBR1 and facilitates cell surface expression of both subunits. Here, we present, to our knowledge, the first crystal structure of an intracellular coiled-coil heterodimer of human GABAB receptor. We found that polar interactions buried within the hydrophobic core determine the specificity of heterodimer pairing. Disruption of the hydrophobic coiled-coil interface with single mutations in either subunit impairs surface expression of GBR1, confirming that the coiled-coil interaction is required to inactivate the adjacent ER retention signal of GBR1. The coiled-coil assembly buries an internalization motif of GBR1 at the heterodimer interface. The ER retention signal of GBR1 is not part of the core coiled-coil structure, suggesting that it is sterically shielded by GBR2 upon heterodimer formation.
| S-EPMC4024898 | biostudies-literature
Project description:The γ-aminobutyric acid (GABA) type B receptor (GABAB-R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABAA receptor, the receptor mediates the neurotransmission of GABA, the main inhibitory neurotransmitter in the central nervous system (CNS). In recent decades, the receptor has been extensively studied with the intention being to understand pathophysiological roles, structural mechanisms and develop drugs. The dysfunction of the receptor is linked to a broad variety of disorders, including anxiety, depression, alcohol addiction, memory and cancer. Despite extensive efforts, few compounds are known to target the receptor, and only the agonist baclofen is approved for clinical use. The receptor is a mandatory heterodimer of the GABAB1 and GABAB2 subunits, and each subunit is composed of an extracellular Venus Flytrap domain (VFT) and a transmembrane domain of seven α-helices (7TM domain). In this review, we briefly present the existing knowledge about the receptor structure, activation and compounds targeting the receptor, emphasizing the role of the receptor in previous and future drug design and discovery efforts.
| S-EPMC7411975 | biostudies-literature
Project description:Initialized from the scaffold of CGP7930, an allosteric agonist of GABAB receptors, a series of noncompetitive antagonists were discovered. Among these compounds, compounds 3, 6, and 14 decreased agonist GABA-induced maximal effect of IP3 production in HEK293 cells overexpressing GABAB receptors and Gqi9 proteins without changing the EC50. Compounds 3, 6, and 14 not only inhibited agonist baclofen-induced ERK1/2 phosphorylation but also blocked CGP7930-induced ERK1/2 phosphorylation in HEK293 cells overexpressing GABAB receptors. The results suggested that compounds 3, 6, and 14 are negative allosteric modulators of GABAB receptors. The representative compound 14 decreased GABA-induced IP3 production with IC50 of 37.9 μM and had no effect on other GPCR Class C members such as mGluR1, mGluR2, and mGluR5. Finally, we showed that compound 14 did not bind to the orthosteric binding sites of GABAB receptors, demonstrating that compound 14 negatively modulated GABAB receptors activity as a negative allosteric modulator.
| S-EPMC4094264 | biostudies-literature
Project description:Tibolone is primarily used for the treatment of climacteric symptoms. Tibolone is rapidly converted into three major metabolites: 3 alpha- and 3beta-hydroxy (OH)-tibolone, which have oestrogenic effects, and the Delta 4-isomer (Delta 4-tibolone), which has progestogenic and androgenic effects. Because tibolone is effective in treating climacteric symptoms, the effects on the brain may be explained by the oestrogenic activity of tibolone. Using whole-cell patch clamp recording, we found previously that 17beta-oestradiol (E(2)) rapidly altered gamma-aminobutyric acid (GABA) neurotransmission in hypothalamic neurones through a membrane oestrogen receptor (mER). E(2) reduced the potency of the GABA(B) receptor agonist baclofen to activate G-protein-coupled, inwardly rectifying K(+) (GIRK) channels in hypothalamic neurones. Therefore, we hypothesised that tibolone may have some rapid effects through the mER and sought to elucidate the signalling pathway of tibolone's action using selective inhibitors and whole cell recording in ovariectomised female guinea pigs and mice. A sub-population of neurones was identified post hoc as pro-opiomelanocortin (POMC) neurones by immunocytochemical staining. Similar to E(2), we have found that tibolone and its active metabolite 3 beta OH-tibolone rapidly reduced the potency of the GABA(B) receptor agonist baclofen to activate GIRK channels in POMC neurones. The effects were blocked by the ER antagonist ICI 182 780. Other metabolites of tibolone (3 alpha OH-tibolone and Delta 4-tibolone) had no effect. Furthermore, tibolone (and 3 beta OH-tibolone) was fully efficacious in ER alpha knockout (KO) and ER beta KO mice to attenuate GABA(B) responses. The effects of tibolone were blocked by phospholipase C inhibitor U73122. However, in contrast to E(2), the effects of tibolone were not blocked by protein kinase C inhibitors or protein kinase A inhibitors. It appears that tibolone (and 3 beta OH-tibolone) activates phospholipase C leading to phosphatidylinositol bisphosphate metabolism and direct alteration of GIRK channel function. Therefore, tibolone may enhance synaptic efficacy through the G(q) signalling pathways of mER in brain circuits that are critical for maintaining homeostatic functions.
| S-EPMC2613946 | biostudies-literature