Advances in the molecular understanding of GABAB receptors

Billinton, Andrew; Ige, Antoinette O; Bolam, J. Paul; White, J. L.; Marshall, Fiona H.; Emson, Piers C.

doi:10.1016/s0166-2236(00)01815-4

Cited by 92 publications

(64 citation statements)

References 52 publications

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“…Upon activation of the G-protein, the G␤␥ complex represses Ca 2ϩ influx by inhibiting Ca 2ϩ channels at presynaptic sites, suppresses neurotransmitter release (Harayama et al, 1998), and triggers the opening of K ϩ channels at the postsynaptic level (Lüscher et al, 1997;Schuler et al, 2001). G␣ i/o subunits modulate the level of cAMP by regulating adenylate cyclase activities at postsynaptic sites, and inhibition of neuronal excitability (Simonds, 1999;Billinton et al, 2001). Interestingly, recent studies suggest that in addition to a role in neuronal excitability and plasticity, GABA B receptor may promote neuronal survival under conditions of metabolic stress or after ischemia (Dave et al, 2005;Kuramoto et al, 2007;Zhang et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

GABA_BReceptor Activation Protects Neurons from Apoptosis via IGF-1 Receptor Transactivation

Tu¹,

Xu²,

Zhang³

et al. 2010

J. Neurosci.

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Section: Introductionmentioning

confidence: 99%

GABA_BReceptor Activation Protects Neurons from Apoptosis via IGF-1 Receptor Transactivation

Tu¹,

Xu²,

Zhang³

et al. 2010

J. Neurosci.

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“…This receptor is involved in numerous physiological processes via the regulation of both GABAergic and glutamatergic synapses at either the pre-or post-synaptic level (1). Accordingly, GABA B receptors are involved in various types of epilepsy, nociception and drug addiction, and spasticity associated with multiple sclerosis (2).…”

mentioning

confidence: 99%

The Heptahelical Domain of GABAB2 Is Activated Directly by CGP7930, a Positive Allosteric Modulator of the GABAB Receptor

Binet

Brajon

Corre

et al. 2004

Journal of Biological Chemistry

194

138

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The ␥-aminobutyric acid, type B (GABA B ) receptor is well recognized as being composed of two subunits, GABA B1 and GABA B2 . Both subunits share structural homology with other class-III G-protein-coupled receptors. They are composed of two main domains: a heptahelical domain (HD) typical of all G-protein-coupled receptors and a large extracellular domain (ECD). Although GABA B1 binds GABA, GABA B2 is required for GABA B1 to reach the cell surface. However, it is still not demonstrated whether the association of these two subunits is always required for function in the brain. Indeed, GABA B2 plays a major role in the coupling of the heteromer to G-proteins, such that it is possible that GABA B2 can transmit a signal in the absence of GABA B1 . Today only ligands interacting with GABA B1 ECD have been identified. Thus, the compounds acting exclusively on the GABA B2 subunit will be helpful in analyzing the specific role of this subunit in the brain. Here, we explored the mechanism of action of CGP7930, a compound described as a positive allosteric regulator of the GABA B receptor. We showed that it activates the wild type GABA B receptor but with a low efficacy. The GABA B2 HD is necessary for this effect, although one cannot exclude that CGP7930 could also bind to GABA B1 . Of interest, CGP7930 could activate GABA B2 expressed alone and is the first described agonist of GABA B2 . Finally, we show that CGP7930 retains its agonist activity on a GABA B2 subunit deleted of its ECD. This demonstrates that the HD of GABA B2 behaves similar to a rhodopsin-like receptor, because it can reach the cell surface alone, can couple to G-protein, and be activated by agonists. These data open new strategies for studying the mechanism of activation of GABA B receptor and examine any possible role of homomeric GABA B2 receptors.

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“…The GABA B receptors belong to the family C of the G-protein-coupled receptor superfamily (Möhler and Fritschy, 1999;Marshall et al, 2000). Two receptors, GABA B(1) and GABA B(2) , have recently been cloned, and several splice variants of both receptors have been identified (Kaupmann et al, 1997(Kaupmann et al, , 1998Jones et al, 1998;White et al, 1998;Pfaff et al, 1999;Billinton et al, 2001).…”

mentioning

confidence: 99%

“…Thus, the only molecular difference between splice variants GABA B(1a) and GABA B(1b) is the presence of two "Sushi domains" upstream of the VFT region in GABA B(1a) that are not found in GABA B(1b) (Kaupmann et al, 1997). The human GABA B(1c) is characterized by the absence of the second Sushi domain compared with GABA B(1a) (Billinton et al, 2001).…”

mentioning

confidence: 99%

The Anticonvulsant Gabapentin (Neurontin) Does Not Act through γ-Aminobutyric Acid-B Receptors

et al. 2002

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The actions of the anticonvulsant gabapentin [1-(aminomethyl)-cyclohexaneacetic acid, Neurontin] have been somewhat enigmatic until recently, when it was claimed to be a ␥-aminobutyric acid-B (GABA B ) receptor agonist acting exclusively at a heterodimeric complex containing the GABA B(1a) splice variant (Mol Pharmacol 2001;59:144 -152). In this study, we have investigated the effects of gabapentin on recombinant GABA B(1a) and GABA B(1b) receptors coexpressed with GABA B(2) in five different functional recombinant assays, its ability to inhibit [ 3 H]GABA binding in a GABA B receptor-selective binding assay using rat synaptic membranes, and its ability to inhibit transient lower esophageal sphincter relaxations in Labrador retriever dogs. Up to a concentration of 1 mM, gabapentin displayed no agonistic effects on either the GABA B(1a,2) or the GABA B(1b,2) heterodimer, when these were expressed in Xenopus laevis oocytes or mammalian cells and assayed by means of electrophysiology, calcium mobilization, inositol phosphate, and fluorometry assays. Gabapentin did not displace [3 H]GABA from GABA B receptor sites in rat synaptic membranes. Finally, in contrast to the classic GABA B receptor agonist baclofen, gabapentin was unable to inhibit transient lower esophageal sphincter relaxations in dogs. Because of high levels of GABA B(1a) in the canine nodose ganglion, this finding indirectly supports the inactivity of gabapentin on the GABA B(1a,2) heterodimer demonstrated in various in vitro assays. In light of these results, we find it highly questionable that gabapentin is a GABA B receptor agonist. Hence, the anticonvulsive effects of the compound have to arise from GABA B receptor-independent mechanisms. This also implies that the first GABA B receptor splice variantselective ligand remains to be discovered.␥-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system, where it exerts its effect through the ionotropic GABA A receptors and the metabotropic GABA B receptors. The GABA B receptors belong to the family C of the G-protein-coupled receptor superfamily (Möhler and Fritschy, 1999;Marshall et al., 2000). Two receptors, GABA B(1) and GABA B(2) , have recently been cloned, and several splice variants of both receptors have been iden-

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Advances in the molecular understanding of GABAB receptors

Cited by 92 publications

References 52 publications

GABA_BReceptor Activation Protects Neurons from Apoptosis via IGF-1 Receptor Transactivation

GABA_BReceptor Activation Protects Neurons from Apoptosis via IGF-1 Receptor Transactivation

The Heptahelical Domain of GABAB2 Is Activated Directly by CGP7930, a Positive Allosteric Modulator of the GABAB Receptor

The Anticonvulsant Gabapentin (Neurontin) Does Not Act through γ-Aminobutyric Acid-B Receptors

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Advances in the molecular understanding of GABAB receptors

Cited by 92 publications

References 52 publications

GABABReceptor Activation Protects Neurons from Apoptosis via IGF-1 Receptor Transactivation

GABABReceptor Activation Protects Neurons from Apoptosis via IGF-1 Receptor Transactivation

The Heptahelical Domain of GABAB2 Is Activated Directly by CGP7930, a Positive Allosteric Modulator of the GABAB Receptor

The Anticonvulsant Gabapentin (Neurontin) Does Not Act through γ-Aminobutyric Acid-B Receptors

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GABA_BReceptor Activation Protects Neurons from Apoptosis via IGF-1 Receptor Transactivation

GABA_BReceptor Activation Protects Neurons from Apoptosis via IGF-1 Receptor Transactivation