Daniela Felice, John F. Cryan, Olivia F. O’Leary,
... ionotropic GABAA and GABAC receptors, and the metabotropic GABAB receptor. This chapter summarizes the studies that have investigated the role of the GABAB receptor in stress-related psychiatric disorders including anxiety and ... clinical and preclinical evidences strongly suggest that the GABAB receptor is a therapeutic candidate for depression and anxiety disorders. However, the clinical development of GABAB receptor-based drugs to treat these disorders has been ... those of agonists. Nevertheless, the discovery of novel GABAB receptor allosteric modulators, and increasing understanding of the influence ...
Tópico(s): Pharmacological
2020 - Springer Science+Business Media | Current topics in behavioral neurosciences
Nobuhito Murai, Yuji Kondo, Shinobu Akuzawa, Takuma Mihara, Nobuyuki Shiraishi, Shuichiro Kakimoto, Mitsuyuki Matsumoto,
The gamma-aminobutyric acid type B (GABAB) receptor agonist, the sodium salt of gamma-hydroxybutyrate (GHB), significantly improved pain, sleep disturbance and fatigue in fibromyalgia (FM) patients. However, the use of GABAB receptor agonists is limited by their undesirable side-effects. To clarify whether GABAB receptor positive allosteric modulator (PAM) approach would achieve analgesia with less side-effects than GABAB receptor agonist in FM, we investigated the potential of a novel GABAB receptor PAM, ASP8062, for FM treatment. We examined the ...
Tópico(s): Fibromyalgia and Chronic Fatigue Syndrome Research
2019 - Elsevier BV | European Journal of Pharmacology
Antón Barreiro‐Iglesias, Daniel Romaus‐Sanjurjo, Marı́a Celina Rodicio,
... and acts through both metabotropic G-protein-coupled GABAB receptors, and ionotropic ligand-gated chloride channel GABAA receptors. ... acts as a pro-regenerative factor by activating GABAB receptors expressed in descending neurons after a complete SCI ... by these receptors in injured neurons. Role of GABAB receptors after CNS injuries: GABAB receptors are obliged heterodimeric G protein-coupled receptors composed ... G-protein response. Once GABA binds to a GABAB receptor, the Gαi protein is activated, which inhibits adenylyl ...
Tópico(s): Neuroendocrine regulation and behavior
2019 - Medknow | Neural Regeneration Research
Khaled Zemoura, Karthik Balakrishnan, Thomas Grampp, Dietmar Benke,
The G protein-coupled GABAB receptors, constituted from GABAB1 and GABAB2 subunits, are important regulators of neuronal excitability by mediating long-lasting inhibition. One factor that ... the strength of inhibition is regulated protein degradation. GABAB receptors are constitutively internalized from the plasma membrane and ... bomb-2 (MIB2) is the signal that sorts GABAB receptors to lysosomes. However, it is unknown how Lys- ... promotes MIB2-mediated Lys-63-linked ubiquitination of GABAB receptors. We found that inhibition of CaMKII in cultured ...
Tópico(s): Neuroscience and Neuropharmacology Research
2018 - Springer Science+Business Media | Molecular Neurobiology
Rebecca Howell, Jason R. Pugh,
Many excitatory synapses co-express presynaptic GABAA and GABAB receptors, despite their opposing actions on synaptic transmission. It ... lasting (>500 ms) inhibition of transmission (mediated by GABAB receptors). When activated just prior to high-frequency trains of stimulation, presynaptic GABAA and GABAB receptors work together to reduce short-term facilitation/enhance ... of synaptic transmission. Inhibition of synaptic transmission by GABAB receptors is more sensitive to GABA than enhancement by GABAA receptors, suggesting GABAB receptors may be activated by ambient GABA or release ...
Tópico(s): Photoreceptor and optogenetics research
2016 - Wiley | The Journal of Physiology
Khaled Zemoura, Claudia Trümpler, Dietmar Benke,
GABAB receptors are heterodimeric G protein-coupled receptors, which control neuronal excitability by mediating prolonged inhibition. The magnitude of GABAB receptor-mediated inhibition essentially depends on the amount of ... However, the factors regulating cell surface expression of GABAB receptors are poorly characterized. Cell surface GABAB receptors are constitutively internalized and either recycled to the ... or degraded in lysosomes. The signal that sorts GABAB receptors to lysosomes is currently unknown. Here we show ...
Tópico(s): Calcium signaling and nucleotide metabolism
2016 - Elsevier BV | Journal of Biological Chemistry
Matthew S. Stratton, Michelle Staros, Tomaž Büdefeld, Brian T. Searcy, Connor P. Nash, Chad Eitel, David L. Carbone, Robert J. Handa, Gregor Majdič, Stuart A. Tobet,
... and the autonomic nervous system. Females lacking functional GABAB receptors because of a genetic disruption of the R1 ... of a temporally restricting pharmacological blockade of the GABAB receptor to a 7-day critical period (E11–E17) during embryonic development. Experiments tested the role of GABAB receptor signaling in fetal development of the PVN and ... specific, 52% increase in cell movement speeds with GABAB receptor antagonist treatment that was consistent with a sex- ... vivo following 7 days of fetal exposure to GABAB receptor antagonist. Anxiety-like and depression-like behaviors, open- ...
Tópico(s): Tryptophan and brain disorders
2014 - Public Library of Science | PLoS ONE
Khaled Zemoura, Dietmar Benke,
... understood. We previously showed that proteasomal degradation of GABAB receptors via the endoplasmic reticulum (ER)-associated protein degradation (ERAD) machinery determines the number of cell surface GABAB receptors and thereby GABAB receptor-mediated neuronal inhibition. Here, we show that proteasomal degradation of GABAB receptors requires the interaction of the GABAB2 C terminus ... of Rpt6 lacking ATPase activity prevented degradation of GABAB receptors but not the removal of Lys(48)-linked ... ERAD activity diminished the interaction of Rtp6 with GABAB receptors resulting in increased total as well as cell ...
Tópico(s): Genetics and Neurodevelopmental Disorders
2014 - Elsevier BV | Journal of Biological Chemistry
Khaled Zemoura, Marisa Schenkel, Mario A. Acuña, Gonzalo E. Yévenes, Hanns Ulrich Zeilhofer, Dietmar Benke,
Metabotropic GABAB receptors are crucial for controlling the excitability of neurons by mediating slow inhibition in the CNS. The strength ... trafficking and degradation mechanisms. Although the mechanisms of GABAB receptor trafficking are studied to some extent, it is ... whether receptor degradation actively controls the number of GABAB receptors available for signaling. Here we tested the hypothesis that proteasomal degradation contributes to the regulation of GABAB receptor expression levels. Blocking proteasomal activity in cultured cortical ...
Tópico(s): Genetics and Neurodevelopmental Disorders
2013 - Elsevier BV | Journal of Biological Chemistry
Hartmut Cuny, Andrew de Faoite, Thuan G. Huynh, Takahiro Yasuda, Géza Berecki, David J. Adams,
... a pathway involving γ-aminobutyric acid type B (GABAB) receptor. However, there is no direct demonstration that functional GABAB receptors are needed for inhibition of the Cav2.2 ... calcium channel currents after transient knockdown of the GABAB receptor using RNA interference. Isolated rat DRG neurons were ... GABAB subunits R1 and R2. Efficient knockdown of GABAB receptor expression at mRNA and protein levels was confirmed ... Vc1.1 and RgIA was significantly reduced in GABAB receptor knockdown DRG neurons. In contrast, neurons transfected with ...
Tópico(s): Pain Mechanisms and Treatments
2012 - Elsevier BV | Journal of Biological Chemistry
Styliani Vlachou, Neil E. Paterson, Sébastien Guery, Klemens Kaupmann, Wolfgang Froestl, Deboshri Banerjee, M. G. Finn, Athina Markou,
... withdrawal and the rewarding effects of acute nicotine. GABAB receptor antagonists exhibit antidepressant-like effects in rodents, whereas GABAB receptor agonists attenuate the rewarding effects of nicotine. Recent studies with GABAB receptor positive modulators showed that these compounds represent potentially ... nicotine dependence because of fewer side-effects than GABAB receptor agonists. Thus, GABAB receptor agonists and antagonists, and GABAB receptor positive modulators may have efficacy as smoking cessation ...
Tópico(s): Tryptophan and brain disorders
2011 - Elsevier BV | European Journal of Pharmacology
Saad Hannan, Megan E. Wilkins, Ebrahim Dehghani-Tafti, Philip Thomas, S. M. BADDELEY, Trevor G. Smart,
γ-Aminobutyric acid type B (GABAB) receptors are important for slow synaptic inhibition in the CNS. The efficacy of inhibition is directly related to the stability of cell surface receptors. For GABAB receptors, heterodimerization between R1 and R2 subunits is critical ... its dominant role in regulating the internalization of GABAB receptors in live cells. To simultaneously study R1a and ... subunits to determine the surface stability of the GABAB receptor. γ-Aminobutyric acid type B (GABAB) receptors are ...
Tópico(s): Lipid Membrane Structure and Behavior
2011 - Elsevier BV | Journal of Biological Chemistry
Saad Hannan, Megan E. Wilkins, Ebrahim Dehghani-Tafti, Philip Thomas, Stuart M. Baddeley, Trevor G. Smart,
γ-Aminobutyric acid type B (GABAB) receptors are important for slow synaptic inhibition in the CNS. The efficacy of inhibition is directly related to the stability of cell surface receptors. For GABAB receptors, heterodimerization between R1 and R2 subunits is critical ... its dominant role in regulating the internalization of GABAB receptors in live cells. To simultaneously study R1a and ... subunits to determine the surface stability of the GABAB receptor. γ-Aminobutyric acid type B (GABAB) receptors are ...
Tópico(s): Cellular transport and secretion
2011 - Elsevier BV | Journal of Biological Chemistry
Bin Luo, Haitao Wang, Yanyan Su, S. H. Wu, Lin Chen,
... we intended to determine whether activation of presynaptic GABAB receptors modulates GABAergic and glutamatergic inputs to the MGB ... presynaptic mechanisms, we blocked the effects of postsynaptic GABAB receptors by filling recording electrodes with the internal solution ... cesium and QX-314. The activation of presynaptic GABAB receptors by exogenous agonist was shown to modulate synaptic ... MGB as demonstrated by that (1) baclofen, a GABAB receptor agonist, reversibly suppressed both inhibitory postsynaptic currents (IPSCs) ...
Tópico(s): Memory and Neural Mechanisms
2011 - Elsevier BV | Hearing Research
Metabotropic GABA type B (GABAB) receptors are abundantly expressed in the rat spinal dorsal horn. Activation of GABAB receptors by exogenous agonists inhibits synaptic transmission, which is believed to underlie the GABAB receptor-mediated analgesia. However, little effort has been made ... GABA might also mediate inhibition by acting on GABAB receptors. In this study, whole-cell recording techniques were ... to study the effect of endogenous GABA on GABAB receptors in substantia gelatinosa (SG) neurons in adult rat ...
Tópico(s): Neuroscience and Neuropharmacology Research
2011 - Elsevier BV | Neuroscience
Claire L. Padgett, Paul A. Slesinger,
GABAB receptors have been found to play a key role in regulating membrane excitability and synaptic transmission in the brain. The GABAB receptor is a G-protein coupled receptor (GPCR) that ... this review, we describe the relationships between the GABAB receptor, its effectors and associated proteins that mediate GABAB receptor function within the brain. We discuss a unique feature of the GABAB receptor, the requirement for heterodimerization to produce functional receptors, ... as an increasing body of evidence that suggests GABAB receptors comprise a macromolecular signaling heterocomplex, critical for efficient ...
Tópico(s): Nicotinic Acetylcholine
2010 - Elsevier BV | Advances in pharmacology
Nicole Guetg, Said Abdel Aziz, Niklaus Holbro, Rostislav Tureček, Tobias Rose, Riad Seddik, Martin Gassmann, Suzette Moes, Paul Jenoe, Thomas G. Oertner, Emilio Casanova, Bernhard Bettler,
GABAB receptors are the G-protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the brain. GABAB receptors are abundant on dendritic spines, where they dampen ... cultured hippocampal neurons promotes dynamin-dependent endocytosis of GABAB receptors. NMDA-dependent internalization of GABAB receptors requires activation of Ca2+/Calmodulin-dependent protein kinase II (CaMKII), which associates with GABAB receptors in vivo and phosphorylates serine 867 (S867) in ... of either CaMKII or phosphorylation of S867 renders GABAB receptors refractory to NMDA-mediated internalization. Time-lapse two- ...
Tópico(s):
2010 - National Academy of Sciences | Proceedings of the National Academy of Sciences
Patrick Maier, Isabel Marin, Thomas Grampp, Andrea Sommer, Dietmar Benke,
Metabotropic GABAB receptors are abundantly expressed at glutamatergic synapses where they control excitability of the synapse. Here, we tested the hypothesis that glutamatergic neurotransmission may regulate GABAB receptors. We found that application of glutamate to cultured cortical neurons led to rapid down-regulation of GABAB receptors via lysosomal degradation. This effect was mimicked by ... extracellular Ca2+ prevented glutamate-induced down-regulation of GABAB receptors, indicating that Ca2+ influx plays a critical role. ...
Tópico(s): Neuroinflammation and Neurodegeneration Mechanisms
2010 - Elsevier BV | Journal of Biological Chemistry
... that primarily mediates postsynaptic inhibition,1 whereas the GABAB receptor is a G-protein-coupled receptor that can ... regions of the NTS, microinjection of GABAA or GABAB receptor agonists increase arterial pressure, presumably attributable to GABAergic ... inputs.4–6 Furthermore, microinjection of GABAA or GABAB receptor antagonists lower arterial pressure, indicating that GABAergic inhibition ... pressor and sympatho-excitatory responses to activation of GABAB receptors are enhanced in spontaneously hypertensive rats (SHR), DOCA- ...
Tópico(s): Nicotinic Acetylcholine
2010 - Lippincott Williams & Wilkins | Hypertension
M. Rives, Claire Vol, Yugo Fukazawa, Norbert Tinel, Eric Trinquet, Mohammed Akli Ayoub, Ryuichi Shigemoto, Jean‐Philippe Pin, Laurent Prézeau,
... We examined the molecular mechanisms responsible for the GABAB receptor-mediated potentiation of the mGlu receptor signalling reported ... the βγ subunits produced by the Gi-coupled GABAB receptor enhance the mGlu-mediated Gq response. Most importantly, ... 2006). In cerebellar Purkinje cells, activation of the GABAB receptor increases calcium responses generated by the mGlu1a receptor ( ... to examine whether the assembly of mGlu1a and GABAB receptors is necessary for their functional crosstalk. Figure 1. ... GABA). Notably, activation of the Gi/o-coupled GABAB receptor did not lead to a significant change in ...
Tópico(s): Biochemical Analysis and Sensing Techniques
2009 - Springer Nature | The EMBO Journal
Philippe Rondard, Siluo Huang, Carine Monnier, Haijun Tu, Bertrand Blanchard, Nadia Oueslati, Fanny Malhaire, Ying Li, Eric Trinquet, Gilles Labesse, Jean‐Philippe Pin, Jianfeng Liu,
Article3 April 2008free access Functioning of the dimeric GABAB receptor extracellular domain revealed by glycan wedge scanning Philippe ... inhibition through both pre- and post-synaptic metabotropic GABAB receptors (Couve et al, 2004; Bettler and Tiao, 2006). GABAB receptors represent promising drug targets for the treatment of ... and Prézeau, 2007). At the structural level, the GABAB receptor is composed of two homologous subunits, GABAB1 and ... in native tissues. Cell-surface trafficking of the GABAB receptor is controlled by an endoplasmic reticulum retention signal ( ...
Tópico(s): Neuropeptides and Animal Physiology
2008 - Springer Nature | The EMBO Journal
Megan E. Wilkins, Xinyan Li, Trevor G. Smart,
GABAB receptors mediate slow synaptic inhibition in the central nervous system and are important for synaptic plasticity as ... in disease. Located at pre- and postsynaptic sites, GABAB receptors will influence cell excitability, but their effectiveness in ... surface membrane. To examine the dynamic behavior of GABAB receptors in GIRK cells and neurons, we have devised ... fixed and live cells. The results indicate that GABAB receptors rapidly turnover in the cell membrane, with the ... dynamic regulation of other G-protein-coupled receptors. GABAB receptors mediate slow synaptic inhibition in the central nervous ...
Tópico(s): Nicotinic Acetylcholine
2008 - Elsevier BV | Journal of Biological Chemistry
Małgorzata Filip, Małgorzata Frankowska, Edmund Przegaliński,
Preclinical and clinical findings indicate that a GABAB receptor agonist baclofen decreases cocaine use. The present study investigated the effects of the GABAB receptor antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid ( ... in male Wistar rats. The effects of the GABAB receptor ligands on cocaine (10 mg/kg)-induced discriminative ... food-maintained responding. The inhibitory effects of the GABAB receptor agonists and the modulator were blocked by SCH ... horizontal activity. We found that pharmacological stimulation of GABAB receptors by direct agonists or allosteric positive modulation reduces ...
Tópico(s): Pain Mechanisms and Treatments
2007 - Elsevier BV | European Journal of Pharmacology
Thomas Grampp, Kathrin Sauter, Branko Marković, Dietmar Benke,
... rapid endocytosis of γ-aminobutyric acid, type B (GABAB) receptors. Therefore, we analyzed internalization of GABAB receptors expressed in HEK 293 cells qualitatively and quantitatively ... of cell surface receptors was detected. Stimulation of GABAB receptors with GABA or baclofen did not enhance endocytosis ... of agonist-induced internalization. The data suggest that GABAB receptors were endocytosed via the classical dynamin- and clathrin- ... results indicate the presence of constitutive internalization of GABAB receptors via clathrin-coated pits, which resulted in lysosomal ...
Tópico(s):
2007 - Elsevier BV | Journal of Biological Chemistry
D. Grahame Hardie, Bruno G. Frenguelli,
... mechanism for this effect involving phosphorylation of the GABAB receptor. The cellular energy-sensing kinase AMPK is known ... mechanism for this effect involving phosphorylation of the GABAB receptor. The nervous system accounts for a high proportion ... AMPK system is neuroprotective and suggesting that the GABAB receptor is a key mediator of this response (see ... pentameric complexes encoded by at least 17 genes, GABAB receptors are heterodimers formed from only 2 gene products ... sites, where they suppress neurotransmitter release. Activation of GABAB receptors thus suppresses neuronal excitation by multiple mechanisms. Moss ...
Tópico(s): Regulation of Appetite and Obesity
2007 - Cell Press | Neuron
Rei Nomura, Yoshikazu Suzuki, Akira Kakizuka, Hisato Jingami,
The γ-aminobutyric acid, type B (GABAB) receptor is a heterodimeric receptor consisting of two complementary subunits, GABAB1 receptor (GBR1) and GABAB2 receptor (GBR2). GBR1 is responsible for GABA binding, ... heterodimeric receptor. The γ-aminobutyric acid, type B (GABAB) receptor is a heterodimeric receptor consisting of two complementary ... to produce fast synaptic inhibition, and the metabotropic GABAB receptor, to elicit a slow and prolonged inhibitory response. The GABAB receptor, a G-protein-coupled receptor (GPCR), modulates neurotransmitter ...
Tópico(s):
2007 - Elsevier BV | Journal of Biological Chemistry
Amy M. Pooler, R. A. Jeffrey McIlhinney,
... movement. Treatment of COS-7 cells with the GABAB receptor agonist baclofen significantly increased its mobile fraction. These ... movement. Treatment of COS-7 cells with the GABAB receptor agonist baclofen significantly increased its mobile fraction. These ... regulated by a region within its C terminus. GABAB receptors are metabotropic receptors for the inhibitory neurotransmitter γ ... isoxazole-4-propionic acid. Pre- and post-synaptic GABAB receptors are coupled to inhibitory G-proteins and can ... movement. To date, however, membrane dynamics of the GABAB receptor have yet to be investigated. In the present ...
Tópico(s): Nicotinic Acetylcholine
2007 - Elsevier BV | Journal of Biological Chemistry
David A. Slattery, John F. Cryan,
... Although it is more than 20 years since GABAB receptors were first postulated to play a role in ... years, a number of new ligands, including specific GABAB receptor antagonists and positive modulators, as well as genetic ... enabled the study of the role of the GABAB receptor in depression and as possible antidepressants. Although initial ... gave rise to the hypothesis that activation of GABAB receptors may induce antidepressant-like effects, growing evidence suggests that it is in fact GABAB receptor antagonists that have antidepressant-like potential. This supposition ...
Tópico(s): Tryptophan and brain disorders
2006 - Wiley | Drug Development Research
Srividya Balasubramanian, Sami R. Fam, Randy A. Hall,
γ-Aminobutyric acid, type B (GABAB) receptors are heterodimeric G protein-coupled receptors that mediate slow inhibitory synaptic transmission in the central nervous system. To identify novel interacting partners that might regulate GABAB receptor (GABABR) functionality, we screened the GABABR2 carboxyl terminus ... decreased receptor stability and attenuated the duration of GABAB receptor signaling. The effects of mutating the GABABR2 carboxyl ... knockdown of endogenous Mupp1. These findings reveal that GABAB receptor stability and signaling can be modulated via GABABR2 ...
Tópico(s): Neurobiology and Insect Physiology Research
2006 - Elsevier BV | Journal of Biological Chemistry
The metabotropic GABAB receptors mediate slow synaptic inhibition and consist of heterodimers of GABAB1 and GABAB2 subunits. The only known molecular diversity of the GABAB receptors arises from the two GABAB1 isoforms, but its ... distinct subcellular localization and physiological action. The metabotropic GABAB receptors mediate slow synaptic inhibition and consist of heterodimers ... subunits. The only known molecular diversity of the GABAB receptors arises from the two GABAB1 isoforms, but its ... also activates slow synaptic inhibition through the metabotropic GABAB receptors, which are coupled to hetertrimeric G proteins. Activation ...
Tópico(s): Photoreceptor and optogenetics research
2006 - Cell Press | Neuron