Molecular diversity, trafficking and subcellular localization of GABAB receptors

Bettler, Bernhard; Tiao, Janice

doi:10.1016/j.pharmthera.2006.03.006

Cited by 145 publications

(107 citation statements)

References 107 publications

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“…Several other proteins interact with the receptor subunits throughout the secretory pathway (e.g. msec7-1, C/EBP homologous protein, Marlin-1, activating transcription factor 4, and G protein-coupled receptor kinase 4) and may block their association temporarily (40). In addition, the ER retention and trafficking properties of GABA B receptors are modulated by the distinct class of GABA A receptors, raising the possibility of physical and functional cross-talk between these ionotropic and metabotropic neurotransmitter receptor systems (41).…”

Section: Discussionmentioning

confidence: 99%

Dendritic Assembly of Heteromeric γ-Aminobutyric Acid Type B Receptor Subunits in Hippocampal Neurons

Ramírez

Vidal

Tello

et al. 2009

Journal of Biological Chemistry

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Understanding the mechanisms that control synaptic efficacy through the availability of neurotransmitter receptors depends on uncovering their specific intracellular trafficking routes. ␥-Aminobutyric acid type B (GABA B ) receptors (GABA B Rs) are obligatory heteromers present at dendritic excitatory and inhibitory postsynaptic sites. It is unknown whether synthesis and assembly of GABA B Rs occur in the somatic endoplasmic reticulum (ER) followed by vesicular transport to dendrites or whether somatic synthesis is followed by independent transport of the subunits for assembly and ER export throughout the somatodendritic compartment. To discriminate between these possibilities we studied the association of GABA B R subunits in dendrites of hippocampal neurons combining live fluorescence microscopy, biochemistry, quantitative colocalization, and bimolecular fluorescent complementation. We demonstrate that GABA B R subunits are segregated and differentially mobile in dendritic intracellular compartments and that a high proportion of non-associated intracellular subunits exist in the brain. Assembled heteromers are preferentially located at the plasma membrane, but blockade of ER exit results in their intracellular accumulation in the cell body and dendrites. We propose that GABA B R subunits assemble in the ER and are exported from the ER throughout the neuron prior to insertion at the plasma membrane. Our results are consistent with a bulk flow of segregated subunits through the ER and rule out a post-Golgi vesicular transport of preassembled GABA B Rs.

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Section: Discussionmentioning

confidence: 99%

Dendritic Assembly of Heteromeric γ-Aminobutyric Acid Type B Receptor Subunits in Hippocampal Neurons

Ramírez

Vidal

Tello

et al. 2009

Journal of Biological Chemistry

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“…Furthermore, GABA B1 can associate with seven-transmembrane proteins differently from GABA B2 and may thereby modulate the signal transduction of other receptor systems (13,14). Using the intracellular C-terminal domains of the GABA B receptor subunits as bait in genetic screens for interactors like the yeast two-hybrid system, a number of proteins ranging from transcription factors and RNA-binding proteins over trafficking factors to cytoskeletal elements and scaffolding proteins were identified (3,15,16). However, the native interactions of the GABA B receptor as an integral membrane protein complex may only be readily uncovered by biochemical isolation of the protein complex from brain membrane preparations followed by mass spectrometry analysis.…”

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confidence: 99%

GABAB Receptor Constituents Revealed by Tandem Affinity Purification from Transgenic Mice

Bartoi

Rigbolt

et al. 2010

Journal of Biological Chemistry

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GABA B receptors function as heterodimeric G-protein-coupled receptors for the neurotransmitter ␥-aminobutyric acid (GABA). Receptor subtypes, based on isoforms of the ligandbinding subunit GABA B1 , are thought to involve a differential set of associated proteins. Here, we describe two mouse lines that allow a straightforward biochemical isolation of GABA B receptors. The transgenic mice express GABA B1 isoforms that contain sequences for a two-step affinity purification, in addition to their endogenous subunit repertoire. Comparative analyses of purified samples from the transgenic mice and wild-type control animals revealed two novel components of the GABA B1 complex. One of the identified proteins, potassium channel tetramerization domain-containing protein 12, associates with heterodimeric GABA B receptors via the GABA B2 subunit. In transfected hippocampal neurons, potassium channel tetramerization domain-containing protein 12 augmented axonal surface targeting of GABA B2 . The mice equipped with tags on GABA B1 facilitate validation and identification of native binding partners of GABA B receptors, providing insight into the molecular mechanisms of synaptic modulation.GABA B receptors convey the metabotropic action of GABA, 2 the main inhibitory neurotransmitter in the brain (1). They are concentrated at axonal boutons of GABAergic and glutamatergic neurons as well as in dendritic spines and shafts at extrasynaptic sites (2). Presynaptic GABA B receptors primarily inhibit calcium channels regulating evoked neurotransmitter release, whereas postsynaptic GABA B receptors mainly open G-protein-regulated inwardly rectifying potassium channels and thereby elicit slow inhibitory postsynaptic potentials. Additionally, GABA B receptor activation decreases the local cAMP level. GABA B receptors function as heteromeric G-protein-coupled receptors consisting of two subunits, GABA B1 and GABA B2 . Heterodimerization is a prerequisite for both surface trafficking of the receptor and ligand-stimulated activation of a G i/o -protein (3).Two N-terminal GABA B1 variants, termed GABA B1a and GABA B1b differing only by a pair of sushi repeats that is exclusively present in GABA B1a , have been identified (4). They originate from the use of alternative transcriptional start sites (3, 5, 6) and underlie functional subtypes of the GABA B receptor with differential localization to pre-and postsynaptic sites in hippocampus and cortex (7-9). Because the sushi repeats are the only difference between GABA B1a and GABA B1b , it is to be expected that proteins interacting with these domains target or retain the GABA B1a isoform to specific microdomains. Consistently, a soluble recombinant protein of the two sushi repeats binds to neuronal membranes with low nanomolar affinity (10). An interaction of one of the two sushi repeats with fibulin-2 has been described (11), but the functional implication remains elusive.Further subtypes of the GABA B receptor may be formed by a compartment-specific interaction of additional proteins, e.g. e...

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“…7−11 GABA B receptors have been implicated in a variety of neurological and psychiatric disorders including nociception, cognitive impairment, epilepsy, spasticity, and drug addiction. 12 The therapeutic effect of GABA B receptors agonist, Lioresal (also known as baclofen), a drug used to treat spasticity in multiple sclerosis patients, is muscle relaxation. 12,13 Its usage is limited for treatment of neurological and psychiatric disorders because of this unwanted, adverse side effect and also its poor ability to penetrate the blood−brain barrier (BBB).…”

mentioning

confidence: 99%

“…12 The therapeutic effect of GABA B receptors agonist, Lioresal (also known as baclofen), a drug used to treat spasticity in multiple sclerosis patients, is muscle relaxation. 12,13 Its usage is limited for treatment of neurological and psychiatric disorders because of this unwanted, adverse side effect and also its poor ability to penetrate the blood−brain barrier (BBB). 14,15 Positive allosteric modulators (PAMs), which interact with GB2 subunit transmembrane domain, can potentiate the activity of GABA B receptors, with improved selectivity and safety.…”

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confidence: 99%

Discovery of a Negative Allosteric Modulator of GABA_B Receptors

Chen

Sun

Zhang

et al. 2014

ACS Med. Chem. Lett.

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Initialized from the scaffold of CGP7930, an allosteric agonist of GABA B 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 GABA B receptors and Gq i9 proteins without changing the EC 50 . 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 GABA B receptors. The results suggested that compounds 3, 6, and 14 are negative allosteric modulators of GABA B receptors. The representative compound 14 decreased GABA-induced IP3 production with IC 50 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 GABA B receptors, demonstrating that compound 14 negatively modulated GABA B receptors activity as a negative allosteric modulator. KEYWORDS: GABA B receptors, negative allosteric modulator, CGP7930, α-keto acid γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the mammalian central nervous system (CNS).

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Molecular diversity, trafficking and subcellular localization of GABAB receptors

Cited by 145 publications

References 107 publications

Dendritic Assembly of Heteromeric γ-Aminobutyric Acid Type B Receptor Subunits in Hippocampal Neurons

Dendritic Assembly of Heteromeric γ-Aminobutyric Acid Type B Receptor Subunits in Hippocampal Neurons

GABAB Receptor Constituents Revealed by Tandem Affinity Purification from Transgenic Mice

Discovery of a Negative Allosteric Modulator of GABA_B Receptors

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Molecular diversity, trafficking and subcellular localization of GABAB receptors

Cited by 145 publications

References 107 publications

Dendritic Assembly of Heteromeric γ-Aminobutyric Acid Type B Receptor Subunits in Hippocampal Neurons

Dendritic Assembly of Heteromeric γ-Aminobutyric Acid Type B Receptor Subunits in Hippocampal Neurons

GABAB Receptor Constituents Revealed by Tandem Affinity Purification from Transgenic Mice

Discovery of a Negative Allosteric Modulator of GABAB Receptors

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Discovery of a Negative Allosteric Modulator of GABA_B Receptors