Molecular Identification of the Human GABABR2: Cell Surface Expression and Coupling to Adenylyl Cyclase in the Absence of GABABR1

Martin, Stella C.; Russek, Shelley J.; Farb, David H.

doi:10.1006/mcne.1999.0741

Cited by 110 publications

(84 citation statements)

References 27 publications

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“…GABA B receptors are heterodimeric G protein-coupled receptors constituted of two different seven-transmembrane proteins termed GABA B1 and GABA B2 (Jones et al, 1998;Kaupmann et al, 1998;Kuner et al, 1999;Martin et al, 1999;Ng et al, 1999;White et al, 1998). Two main variants of GABA B1 that differ in their N-terminal domain are generated by alternative promoter usage (Steiger et al, 2004) and give rise to two GABA B receptor subtypes, GABA B1a /GABA B2 and GABA B1b /GABA B2 .…”

Section: Introductionmentioning

confidence: 99%

Constitutive, agonist-accelerated, recycling and lysosomal degradation of GABAB receptors in cortical neurons

Grampp

Notz

Broll

et al. 2008

Molecular and Cellular Neuroscience

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Endocytosis is considered as an important mechanism for regulating cell surface numbers and thereby signaling strength of G protein-coupled receptors. Currently, little is known about the endocytotic pathways of GABA B receptors in neurons. Here we report that GABA B receptors are constitutively internalized presumably via clathrin-dependent endocytosis in cultured cortical neurons. Colocalization of GABA B receptors with endosomal marker proteins indicated sorting of GABA B receptors from early endosomes to recycling endosomes and to lysosomes. Cell surface biotinylation experiments revealed fast constitutive recycling

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Section: Introductionmentioning

confidence: 99%

Constitutive, agonist-accelerated, recycling and lysosomal degradation of GABAB receptors in cortical neurons

Grampp

Notz

Broll

et al. 2008

Molecular and Cellular Neuroscience

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“…Of these regions, that on chromosome 9q22-23 appears to be interesting because three additional studies reported a possible linkage, at a nominally significant level, with smoking behaviors (Bergen et al, 1999;Bierut et al, 2004;Gelernter et al, 2004). The genes for both g-Aminobutyric acid (GABA) B receptor subunit 2 (GPR51) and neurotrophic tyrosine kinase receptor type 2 (NTRK2) have been mapped within this linkage region (Nakagawara et al, 1995;Valent et al, 1997;Martin et al, 1999) and suggested to play a significant role in drug addiction. To determine if these two genes are involved in the etiology of ND, we conducted family-based association studies using an independent cohort recruited by us during 1999-2004 and found that these two genes indeed are significantly associated with ND (Beuten et al, 2005a;Beuten et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Regulation by Nicotine of Gpr51 and Ntrk2 Expression in Various Rat Brain Regions

Sun

Huang

Hwang

et al. 2006

Neuropsychopharmacol

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Our previous genetic studies demonstrated that variants of the g-Aminobutyric acid B receptor subunit 2 (GPR51) and neurotrophic tyrosine kinase receptor type 2 (NTRK2) genes are significantly associated with nicotine dependence (ND) in smokers. However, whether such genetic associations lead to changes in the expression of the two genes in response to nicotine remains undetermined. In this study, we investigated the regulatory effect of nicotine on the expression of Gpr51 and Ntrk2 in seven rat brain regions during the administration of nicotine in a daily dose of 3.15 mg/kg for 7 days. With quantitative real-time RT-PCR, we found that nicotine increased the mRNA of Gpr51 by 70, 78, and 32% in the amygdala, striatum, and prefrontal cortex (PFC), respectively, but decreased by 54% in the nucleus accumbens (NA). The Gpr51 protein was upregulated by nicotine in the amygdala (26%), striatum (73%), PFC (28%), and medial basal hypothalamus (MBH; 19%) but downregulated in the NA (À72%). Similarly, the mRNA level of Ntrk2 was enhanced by nicotine in the striatum (86%) and PFC (38%), but decreased in the NA (À46%) and ventral tegmental area (VTA; À49%). A significant change in protein expression was also obtained for Ntrk2 in the PFC (24%), MBH (33%), NA (À33%), and VTA (À70%). Interestingly, these two genes showed a closely coordinated expression pattern in response to nicotine in most of the brain regions examined. In summary, our results demonstrate that the expression of Gpr51 and Ntrk2 is significantly regulated by nicotine at both the mRNA and protein levels in various brain regions, which provides further evidence that these two genes are involved in the etiology of ND, as reported in our previous genetic association studies in humans.

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“…Disruption of GABA B receptor-mediated synaptic pathways has been implicated in many diseases, including neuropathic pain, spasticity, drug addiction, schizophrenia, and epilepsy Calver et al, 2002). Formation of fully functional GABA B receptors requires the coassembly of GABA B R1 and GABA B R2 subunits (Kaupmann et al, 1997(Kaupmann et al, , 1998aJones et al, 1998;White et al, 1998;Kuner et al, 1999;Martin et al, 1999). Multiple isoforms of human GABA B R1 (GABA B R1a, GABA B R1b, GABA B R1c, and GABA B R1e) have been described, but only one GABA B R2 has been identified (Martin et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

cAMP Response Element-Binding Protein, Activating Transcription Factor-4, and Upstream Stimulatory Factor Differentially Control Hippocampal GABA_BR1a and GABA_BR1b Subunit Gene Expression through Alternative Promoters

Steiger

Bandyopadhyay²,

Farb³

et al. 2004

J. Neurosci.

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Expression of metabotropic GABA B receptors is essential for slow inhibitory synaptic transmission in the CNS, and disruption of GABA B receptor-mediated responses has been associated with several disorders, including neuropathic pain and epilepsy. The location of GABA B receptors in neurons determines their specific role in synaptic transmission, and it is believed that sorting of subunit isoforms, GABA B R1a and GABA B R1b, to presynaptic or postsynaptic membranes helps to determine this role. GABA B R1a and GABA B R1b are thought to arise by alternative splicing of heteronuclear RNA. We now demonstrate that alternative promoters, rather than alternative splicing, produce GABA B R1a and GABA B R1b isoforms. Our data further show that subunit gene expression in hippocampal neurons is mediated by the cAMP response element-binding protein (CREB) by binding to unique cAMP response elements in the alternative promoter regions. Double-stranded oligonucleotide decoys selectively alter levels of endogenous GABA B R1a and GABA B R1b in primary hippocampal neurons, and CREB knock-out mice show changes in levels of GABA B R1a and GABA B R1b transcripts, consistent with decoy competition experiments. These results demonstrate a critical role of CREB in transcriptional mechanisms that control GABA B R1 subunit levels in vivo. In addition, the CREB-related factor activating transcription factor-4 (ATF4) has been shown to interact directly with GABA B R1 in neurons, and we show that ATF4 differentially regulates GABA B R1a and GABA B R1b promoter activity. These results, together with our finding that the depolarization-sensitive upstream stimulatory factor (USF) binds to a composite CREB/ATF4/USF regulatory element only in the absence of CREB binding, indicate that selective control of alternative GABA B R1 promoters by CREB, ATF4, and USF may dynamically regulate expression of their gene products in the nervous system.

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Molecular Identification of the Human GABABR2: Cell Surface Expression and Coupling to Adenylyl Cyclase in the Absence of GABABR1

Cited by 110 publications

References 27 publications

Constitutive, agonist-accelerated, recycling and lysosomal degradation of GABAB receptors in cortical neurons

Constitutive, agonist-accelerated, recycling and lysosomal degradation of GABAB receptors in cortical neurons

Regulation by Nicotine of Gpr51 and Ntrk2 Expression in Various Rat Brain Regions

cAMP Response Element-Binding Protein, Activating Transcription Factor-4, and Upstream Stimulatory Factor Differentially Control Hippocampal GABA_BR1a and GABA_BR1b Subunit Gene Expression through Alternative Promoters

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Molecular Identification of the Human GABABR2: Cell Surface Expression and Coupling to Adenylyl Cyclase in the Absence of GABABR1

Cited by 110 publications

References 27 publications

Constitutive, agonist-accelerated, recycling and lysosomal degradation of GABAB receptors in cortical neurons

Constitutive, agonist-accelerated, recycling and lysosomal degradation of GABAB receptors in cortical neurons

Regulation by Nicotine of Gpr51 and Ntrk2 Expression in Various Rat Brain Regions

cAMP Response Element-Binding Protein, Activating Transcription Factor-4, and Upstream Stimulatory Factor Differentially Control Hippocampal GABABR1a and GABABR1b Subunit Gene Expression through Alternative Promoters

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Product

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About

cAMP Response Element-Binding Protein, Activating Transcription Factor-4, and Upstream Stimulatory Factor Differentially Control Hippocampal GABA_BR1a and GABA_BR1b Subunit Gene Expression through Alternative Promoters