Astrocytic GABA receptors

Fraser, Douglas D.; Mudrick‐Donnon, Lori A.; MacVicar, Brian A.

doi:10.1002/glia.440110203

Cited by 106 publications

(67 citation statements)

References 78 publications

(130 reference statements)

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“…Previous studies have shown that substantial amounts of endozepines are spontaneously released by astrocytes (Lamacz et al, 1996) and that glial cells express both GABA A and GABA B receptors (Hösli and Hösli, 1990;Fraser et al, 1994;Bureau et al, 1995). The present data reveal that, at low concentrations (10 Ϫ7 to 10 Ϫ5 M), GABA provokes a dose-dependent inhibition of endozepine release by cultured rat astrocytes.…”

Section: Discussionsupporting

confidence: 45%

GABA inhibits endozepine release from cultured rat astrocytes

Patte

Gandolfo

Leprince

et al. 1999

Glia

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In the mammalian brain, the endogenous ligands for benzodiazepine receptors (also called endozepines) are predominantly synthesized by glial cells. It has recently been reported that rat astrocytes in primary culture release substantial amounts of endozepines. The aim of the present study was to investigate the possible involvement of GABA in the control of endozepine release. Exposure of cultured rat astrocytes to GABA (10−7 to 10−5 M) induced a dose‐related inhibition of endozepine secretion. At higher doses (3 × 10−5 to 10−3 M), the effect of GABA gradually diminished. The inhibitory effect of GABA (10−5 M) was mimicked by the GABAB receptor agonist baclofen (10−5 M). In contrast, the GABAA receptor agonists 3APS and isoguvacine (10−5 M each) did not modify endozepine release. The inhibition of endozepine secretion evoked by GABA and baclofen (10−5 M each) was totally abrogated by the specific GABAB receptor antagonist phaclofen (10−4 M). GABA and baclofen caused a significant inhibition of forskolin‐evoked production of cAMP in astrocytes and this effect was abolished in the presence of phaclofen. In contrast, isoguvacine had no effect on cAMP production. Exposure of astrocytes to dbcAMP induced a time‐ and dose‐dependent stimulation of endozepine release. These data indicate that GABA, acting through GABAB receptors negatively coupled to adenylyl cyclase, inhibits endozepine release from cultured rat astrocytes. The secretion of endozepines thus appears to be a valuable marker to monitor astrocyte activity. GLIA 25:404–411, 1999. © 1999 Wiley‐Liss, Inc.

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Section: Discussionsupporting

confidence: 45%

GABA inhibits endozepine release from cultured rat astrocytes

Patte

Gandolfo

Leprince

et al. 1999

Glia

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“…In addition to their classical role as ligand-gated chloride channels of the postsynapse, electrophysiological studies have demonstrated functional expression of GlyR chloride channels (50) and GABA A receptors (51) in astrocytes and other nonsynaptic cells. Due to a lack of synaptic interactions of these cells, ligand-gated ion channels have been proposed to be involved in other functions, such as regulation of cell volume (52), pH (53), and cell proliferation (54).…”

Section: Discussionmentioning

confidence: 99%

A Novel Glycine Receptor β Subunit Splice Variant Predicts an Unorthodox Transmembrane Topology

Oertel

Villmann

Kettenmann

et al. 2007

Journal of Biological Chemistry

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The inhibitory glycine receptor is a ligand-gated ion channel with a pentameric assembly from ligand binding ␣ and structural ␤ subunits. In addition to ␣ subunit gene variants (␣1-␣4) and developmental alterations in subunit composition of the receptor protein complex, alternative splicing of ␣ subunits has been found to contribute to glycine receptor heterogeneity. Here, we describe a novel splice variant of the glycine receptor ␤ subunit from mouse central nervous system, prevailing in macroglial cells, predominantly in astrocytes and extraneural tissues. As predicted by its cDNA sequence, the novel subunit ␤⌬7 lacks amino acid positions 251-302 encoded by exon 7 of the Glrb gene. Transcripts and antigen of ␤⌬7 were detected in cerebral cortex, liver, and heart. Lack of exon 7 results in a profoundly altered prediction of transmembrane topology as ␤⌬7 lacks TM1 and TM2 present in the full-length variant. Despite these topological alterations, in vitro studies showed that the ␤⌬7 polypeptide integrates into the plasma membrane, forming receptor complexes with the ␣1 subunit and gephyrin. Our data demonstrate that a topology deviating from the classical four transmembrane-fold is compatible with formation of glycine receptor protein complexes. However, co-expression of ␣1 with ␤⌬7 subunits did not change glycine receptor channel properties. Rather, the high level of expression in non-neuronal cells having intimate contact with synaptic regions may account for a yet unknown function of this splice variant ␤⌬7 in glycinergic neurotransmission. Glycine receptors (GlyRs)2 belong to the superfamily of Cysloop receptors, which also include nicotinic acetylcholine receptors, ionotropic ␥-aminobutyric acid receptors (GABA A and GABA C ), and the ionotropic serotonin receptor subtype 5HT 3 (1). GlyRs are pentameric assemblies of five subunits surrounding a central ion-conducting pore that mediates rapid inhibitory neurotransmission in the spinal cord and brainstem (2, 3). Common features of all Cys-loop receptor subunits include four transmembrane regions (TM1-TM4), where TM2 forms the ion channel pore, and a large extracellular N-terminal ligand-binding domain. This domain shows significant structural homology to the acetylcholine-binding protein of Lymnaea stagnalis (4), a member of the immunoglobulin-like superfamily of proteins. By association of ␤ subunits with the intracellular anchor protein gephyrin, GlyRs are clustered at the postsynaptic membrane. The gephyrin binding motif of the ␤ subunit polypeptide has been mapped to the long intracellular TM3-4 loop (5-9).The GlyR ␤ subunit gene is widely transcribed throughout the central nervous system of neonatal and adult rodents. Starting at embryonic day 14, ␤ transcripts are first detectable by in situ hybridization in rat spinal cord and telencephalon (10, 11). Expression of the ligand binding ␣ subunit variants (␣1-␣4) is highly regulated during development (12, 13). Further GlyR subunit heterogeneity is generated by alternative splicing and RNA editing (␣1 and ␣...

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“…Several lines of evidence suggest the presence of GABA B receptors in astrocytes in vivo (Fraser et al, 1994;Kang et al, 1998;Bekar et al, 1999;Sun and Chiu, 1999;Charles et al, 2003;Queva et al, 2003). With immunohistochemical techniques, this is not easily assessed, because secondary antibodies frequently label glial cells, especially in the white matter.…”

Section: Methodological Considerationsmentioning

confidence: 97%

Independent maturation of the GABA_B receptor subunits GABA_B1 and GABA_B2 during postnatal development in rodent brain

Fritschy

Sidler

Parpan

et al. 2004

J of Comparative Neurology

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GABA(B) receptors mediate slow inhibitory GABAergic neurotransmission. They are encoded by two distinct subunits, GABA(B1) (GBR1) and GABA(B2) (GBR2), with two major isoforms of GBR1, GBR1a and GBR1b, arising from differential promoter usage. Heterodimerization of GBR1 and GBR2 is essential for GABA(B) receptor function, as shown in recombinant expression systems and in GBR1(-/-) mice. GABA(B) receptors are highly expressed during ontogeny, prior to synaptogenesis, but their developmental function remains elusive. Here we investigated the postnatal development of GABA(B) receptors in rodent brain, focusing on potential differences in the spatial and temporal expression pattern of GBR1 and GBR2. Immunohistochemistry with subunit-specific antibodies revealed a widespread staining for GBR1a and GBR2 in neonatal rodent brain. During the first 2 weeks, these two subunits exhibited largely overlapping regional distribution, but with profound distinctions in cellular and subcellular localization. The adult-like pattern was established during the third week, with a prominent up-regulation of GBR1b, extensively codistributed with GBR2. Several unexpected features were noted at early stages, notably, a selective GBR2 staining of axonal tracts, such as the corticothalamic projection, and a prominent GBR1 expression in astrocytes. The specificity of the antibody labeling was verified in GBR1- and GBR2-knockout mice. In addition, the analysis of these mutants revealed a partial preservation of GBR2 staining in GBR1(-/-) mice and vice versa. Altogether, the results suggest a functional role for GBR1 and GBR2 proteins in immature brain in addition to their contribution to dimeric GABA(B) receptor complexes.

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Astrocytic GABA receptors

Cited by 106 publications

References 78 publications

GABA inhibits endozepine release from cultured rat astrocytes

GABA inhibits endozepine release from cultured rat astrocytes

A Novel Glycine Receptor β Subunit Splice Variant Predicts an Unorthodox Transmembrane Topology

Independent maturation of the GABA_B receptor subunits GABA_B1 and GABA_B2 during postnatal development in rodent brain

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Astrocytic GABA receptors

Cited by 106 publications

References 78 publications

GABA inhibits endozepine release from cultured rat astrocytes

GABA inhibits endozepine release from cultured rat astrocytes

A Novel Glycine Receptor β Subunit Splice Variant Predicts an Unorthodox Transmembrane Topology

Independent maturation of the GABAB receptor subunits GABAB1 and GABAB2 during postnatal development in rodent brain

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Independent maturation of the GABA_B receptor subunits GABA_B1 and GABA_B2 during postnatal development in rodent brain