Cloning of a Novel G-Protein-Coupled Receptor GPR 51 Resembling GABABReceptors Expressed Predominantly in Nervous Tissues and Mapped Proximal to the Hereditary Sensory Neuropathy Type 1 Locus on Chromosome 9

Ng, Gordon; McDonald, Terrence; Bonnert, Timothy P.; Rigby, Michael; Heavens, R.P.; Whiting, Paul; Chateauneuf, Anne; Coulombe, Nathalie; Kargman, Stacia; Caskey, Thomas; Evans, Jilly F.; O’Neill, Gary P.; Liu, Qingyun

doi:10.1006/geno.1998.5706

Cited by 17 publications

(19 citation statements)

References 22 publications

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“…For colocalization studies the rat gb1 probe was digoxigenin-labeled and developed using anti-digoxigenin horseradish peroxidase, the tyramide signal amplification method and biotinyl tyramide followed by streptavidin-conjugated CY3 (C). and gb1 receptor mRNA (10). In situ hybridization in adjacent coronal sections of rat parietal cortex using 35 S-labeled antisense riboprobes indicates that mRNAs for both gb1 and gb2 receptors are coexpressed in this brain region (Fig.…”

Section: Resultsmentioning

confidence: 90%

“…Two independently derived cDNAs of human gb2 (GenBank TM accession numbers AF069755 and AF056085, the former having previously been called GPR51 (10)) were used to make expression constructs. A N-terminal FLAG-tagged hgb2/pcDNA3.1 construct encoding a modified influenza hemaglutinin signal sequence (MKTIIALSYIFCLVFA) followed by an antigenic FLAG (DYKDDDDK) epitope was generated by PCR (10).…”

Section: Methodsmentioning

confidence: 99%

“…A N-terminal FLAG-tagged hgb2/pcDNA3.1 construct encoding a modified influenza hemaglutinin signal sequence (MKTIIALSYIFCLVFA) followed by an antigenic FLAG (DYKDDDDK) epitope was generated by PCR (10). The hgb2 construct used for expression in 293 cells was the coding sequence from GenBank TM accession number AF056085 with the C-terminal splice variant of GenBank TM accession number AF095723 3 inserted into pcDNA3.1 in a manner similar to that for the rat gb1a.…”

Section: Methodsmentioning

confidence: 99%

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Identification of a GABAB Receptor Subunit, gb2, Required for Functional GABAB Receptor Activity

Clark

Coulombe

et al. 1999

Journal of Biological Chemistry

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121

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G protein-coupled receptors are commonly thought to bind their cognate ligands and elicit functional responses primarily as monomeric receptors. In studying the recombinant ␥-aminobutyric acid, type B (GABA B ) receptor (gb1a) and a GABA B -like orphan receptor (gb2), we observed that both receptors are functionally inactive when expressed individually in multiple heterologous systems. Characterization of the tissue distribution of each of the receptors by in situ hybridization histochemistry in rat brain revealed co-localization of gb1 and gb2 transcripts in many brain regions, suggesting the hypothesis that gb1 and gb2 may interact in vivo. In three established functional systems (inwardly rectifying K ؉ channel currents in Xenopus oocytes, melanophore pigment aggregation, and direct cAMP measurements in HEK-293 cells), GABA mediated a functional response in cells coexpressing gb1a and gb2 but not in cells expressing either receptor individually. This GABA activity could be blocked with the GABA B receptor antagonist CGP71872. 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 GABA B receptor.Metabotropic GABA B 1 receptors were first distinguished pharmacologically by Hill and Bowery (1). Kaupmann et al. (2) recently cloned two alternatively spliced forms of the GABA B receptor, termed gb1a and gb1b, which belong to the G proteincoupled receptor superfamily and are most closely related to the metabotropic glutamate receptors. Although native GABA B receptors are reported to activate inwardly rectifying K ϩ channels (Kir) (3), recombinant gb1a receptors coexpressed with Kir channels in Xenopus oocytes failed to be functionally active (2,4,12). A recent report has shown that recombinant GABA B receptors fail to couple to effector pathways in a variety of non-neuronal and neuronal cell types, suggesting that additional cellular component(s) are required (4). Failure to show GABA B receptor function coupled with previous reports that GPCRs can undergo dimerization (5-8), suggested that heterodimerization may be important for GABA B receptor function. Furthermore, receptor heterodimerization appears to rescue function of mutated or chimeric muscarinic and adrenergic receptors (9). We report here that coexpression of gb1 and gb2 receptors are necessary for the formation of functional GABA B receptors and result in heterodimerization. EXPERIMENTAL PROCEDURESExpression Constructs for gb1a and gb2 Receptors-The murine gb1a (mgb1a) cDNA was constructed from two expressed sequence tags (IMAGE Consortium clone identification numbers 472408 and 319196), combined by standard PCR methods, and subcloned into the pCINeo (Stratagene) and pcDNA3.1 (Invitrogen) vectors.2 The rat gb1a receptor was obtained by PCR of rat brain cDNA using oligonucleotide primers based on the published sequence (Ref. 2; GenBank TM accession number Y10369) and subcloned into pcDNA3.1.Two independently der...

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Section: Resultsmentioning

confidence: 90%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Identification of a GABAB Receptor Subunit, gb2, Required for Functional GABAB Receptor Activity

Clark

Coulombe

et al. 1999

Journal of Biological Chemistry

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200

121

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“…The GABA B (1) and GABA B (2) genes map to human chromosomes 6p21.3 and 9q22, respectively (123,238). Given the potential implication of GABA B receptors in the etiology of epilepsies (see sect.…”

Section: E Genetic Linkage Studiesmentioning

confidence: 99%

“…However, GABA B(1) polymorphisms do not account for the genetic variance of alcohol dependence, nor is there an indication for increased vulnerability to panic disorders. The GABA B (2) gene maps in the vicinity to the locus for hereditary sensory neuropathy type-1 (HSN-1) (238). A possible involvement of GABA B (2) in the etiology of HSN- 1 has not yet been investigated.…”

Section: E Genetic Linkage Studiesmentioning

confidence: 99%

Molecular Structure and Physiological Functions of GABA_BReceptors

Bettler

Kaupmann

Mosbacher

et al. 2004

Physiological Reviews

799

720

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GABAB receptors are broadly expressed in the nervous system and have been implicated in a wide variety of neurological and psychiatric disorders. The cloning of the first GABAB receptor cDNAs in 1997 revived interest in these receptors and their potential as therapeutic targets. With the availability of molecular tools, rapid progress was made in our understanding of the GABAB system. This led to the surprising discovery that GABAB receptors need to assemble from distinct subunits to function and provided exciting new insights into the structure of G protein-coupled receptors (GPCRs) in general. As a consequence of this discovery, it is now widely accepted that GPCRs can exist as heterodimers. The cloning of GABAB receptors allowed some important questions in the field to be answered. It is now clear that molecular studies do not support the existence of pharmacologically distinct GABAB receptors, as predicted by work on native receptors. Advances were also made in clarifying the relationship between GABAB receptors and the receptors for γ-hydroxybutyrate, an emerging drug of abuse. There are now the first indications linking GABAB receptor polymorphisms to epilepsy. Significantly, the cloning of GABAB receptors enabled identification of the first allosteric GABAB receptor compounds, which is expected to broaden the spectrum of therapeutic applications. Here we review current concepts on the molecular composition and function of GABAB receptors and discuss ongoing drug-discovery efforts.

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MetabotropicGABAReceptors

Gassmann

Bettler

2007

Handbook of Contemporary Neuropharmacology

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We provide an overview on the current knowledge on protein interactions with GABA B receptors. Furthermore, we review recent studies that tried to establish a link between polymorphisms in GABA B genes and congenital human diseases. Taking recent developments in the field into account, we also touch on the most promising indications for GABA B drugs. Last but not least, the cloned receptors were used to establish high‐throughput compound screens based on functional assays, which yielded the first allosteric compounds acting at GABA B receptors. The features of these compounds will be discussed.

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Cloning of a Novel G-Protein-Coupled Receptor GPR 51 Resembling GABABReceptors Expressed Predominantly in Nervous Tissues and Mapped Proximal to the Hereditary Sensory Neuropathy Type 1 Locus on Chromosome 9

Cited by 17 publications

References 22 publications

Identification of a GABAB Receptor Subunit, gb2, Required for Functional GABAB Receptor Activity

Identification of a GABAB Receptor Subunit, gb2, Required for Functional GABAB Receptor Activity

Molecular Structure and Physiological Functions of GABA_BReceptors

MetabotropicGABAReceptors

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Cloning of a Novel G-Protein-Coupled Receptor GPR 51 Resembling GABABReceptors Expressed Predominantly in Nervous Tissues and Mapped Proximal to the Hereditary Sensory Neuropathy Type 1 Locus on Chromosome 9

Cited by 17 publications

References 22 publications

Identification of a GABAB Receptor Subunit, gb2, Required for Functional GABAB Receptor Activity

Identification of a GABAB Receptor Subunit, gb2, Required for Functional GABAB Receptor Activity

Molecular Structure and Physiological Functions of GABABReceptors

MetabotropicGABAReceptors

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Molecular Structure and Physiological Functions of GABA_BReceptors