GABAB receptor activation enhances mGluR-mediated responses at cerebellar excitatory synapses

Hirono, Moritoshi; Yoshioka, Tohru; Konishi, Shiro

doi:10.1038/nn764

Cited by 155 publications

(160 citation statements)

References 48 publications

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“…The results in Fig. 4 clearly show that the mGluR1 sensitization studied here is independent of G i/o proteins and distinct from the G i/o protein-dependent augmentation of mGluR1 response (8).…”

Section: The Ca O 2؉ -Dependent Mglur1 Sensitization Does Not Requirementioning

confidence: 55%

“…In most neurons, GABA B R is coupled to its effectors via G i/o proteins (4). A previous study (8) reported that GABA B R stimulation with GABA analogs results in G i/o protein-dependent augmentation of mGluR1 responses. To examine the G i/o protein-dependence of the mGluR1 sensitization studied here, we pretreated Purkinje cells with PTX (500 ng͞ml, Ն13 h; Fig.…”

Section: The Ca O 2؉ -Dependent Mglur1 Sensitization Does Not Requirementioning

confidence: 95%

“…However, in some central neurons including cerebellar Purkinje cells, postsynaptic GABA B Rs are concentrated perisynaptically at the excitatory synapses and present sparsely at the inhibitory synapses (5)(6)(7). Because GABA B Rs are insensitive to the excitatory neurotransmitter glutamate, a physiological role of GABA B R at excitatory synapses was assumed to depend on ␥-aminobutyric acid (GABA) spillover from neighboring inhibitory synapses (8,9).…”

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confidence: 99%

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Ca ²⁺ activity at GABA _B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

Tabata

Araishi

Hashimoto

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Type B ␥-aminobutyric acid receptor (GABABR) is a G proteincoupled receptor that regulates neurotransmitter release and neuronal excitability throughout the brain. In various neurons, GABA BRs are concentrated at excitatory synapses. Although these receptors are assumed to respond to GABA spillover from neighboring inhibitory synapses, their function is not fully understood. Here we show a previously undescribed function of GABA BR exerted independent of GABA. In cerebellar Purkinje cells, interaction of GABA BR with extracellular Ca 2؉ (Ca o 2؉ ) leads to a constitutive increase in the glutamate sensitivity of metabotropic glutamate receptor 1 (mGluR1). mGluR1 sensitization is clearly mediated by GABA BR because it is absent in GABABR1 subunitknockout cells. However, the mGluR1 sensitization does not require G i/o proteins that mediate the GABABR's classical functions. Moreover, coimmunoprecipitation reveals complex formation between GABA BR and mGluR1 in the cerebellum. These findings demonstrate that GABA BR can act as Ca o 2؉ -dependent cofactors to enhance neuronal metabotropic glutamate signaling.T he type B ␥-aminobutyric acid receptor (GABA B R) is a G protein-coupled receptor (GPCR) distributed throughout the brain (1-3). GABA B R regulates neurotransmitter release and neuronal excitability via G i/o proteins (4). In the classic view, GABA B R responds to GABA released from inhibitory presynaptic terminals (4). However, in some central neurons including cerebellar Purkinje cells, postsynaptic GABA B Rs are concentrated perisynaptically at the excitatory synapses and present sparsely at the inhibitory synapses (5-7). Because GABA B Rs are insensitive to the excitatory neurotransmitter glutamate, a physiological role of GABA B R at excitatory synapses was assumed to depend on ␥-aminobutyric acid (GABA) spillover from neighboring inhibitory synapses (8, 9).The extracellular domain of GABA B R has an amino acid sequence homology to that of Ca 2ϩ -sensing receptor (CaR) (10). Some studies in the heterologous expression systems (11,12) revealed that GABA B R indeed interacts with extracellular Ca 2ϩ (Ca o 2ϩ ). Point mutation experiments indicate that the proximity of the GABA-binding site of GABA B R1 subunit (GBR1) is responsible for this interaction (11). Although Ca o 2ϩ -GABA B R interaction does not activate G proteins (12), it causes a remarkable conformational change of GABA B R as Ca o 2ϩ allosterically shifts GABA-GABA B R affinity (11,12 (22-25), and developmental synapse elimination (24, 26). In cerebellar Purkinje cells, mGluR1 colocalizes with GABA B R at the annuli of the dendritic spines innervated by excitatory parallel fibers (7,27). We have previously shown that mGluR1 signaling in Purkinje cells is enhanced as a consequence of interaction between Ca o 2ϩ and an unknown surface molecule(s) (28). For the reasons mentioned above, we considered GABA B R as a likely candidate for such a surface molecule.In Purkinje cells, mGluR1 outnumbers the other mGluR subtypes (16) and operates an inward ca...

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Section: The Ca O 2؉ -Dependent Mglur1 Sensitization Does Not Requirementioning

confidence: 55%

Section: The Ca O 2؉ -Dependent Mglur1 Sensitization Does Not Requirementioning

confidence: 95%

mentioning

confidence: 99%

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Ca ²⁺ activity at GABA _B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

Tabata

Araishi

Hashimoto

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…Impaired GABAergic signaling in FXS might partially be caused by decreased expression of GABA receptors in these brain areas (El Idrissi et al, 2005;D'Hulst et al, 2006;Adusei et al, 2010). On the other hand, it could be a secondary effect of dysregulated mGlu 1/5 -dependent signaling, because these two receptors were shown to crosstalk in several different brain areas (Hirono et al, 2001;Deng et al, 2010;Kolaj and Renaud, 2010). The exact mechanisms of reduced GABA-mediated signaling in FXS are currently unclear; nevertheless, results from animal studies and clinical trials suggest that GABA agonists are suitable to treat FXS-associated symptoms (Chang et al, 2008;Heulens et al, 2010;Olmos-Serrano et al, 2010).…”

Section: Altered Signaling Of Other Membrane Receptorsmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

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Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS.

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“…In the cerebellum, glutamate released from parallel fiber synapses onto Purkinje cells causes a slow EPSC mediated by mGlu receptors and G proteins (Hirono et al 1998(Hirono et al , 2001Tempia et al 1998). This current can be mimicked by ACPD or DHPG (Hartmann et al 2008), but unlike other Group Imediated responses is resistant or partially resistant to strong intracellular Ca 2+ buffering (BAPTA), inhibition of PLC (U-73122), and inhibition of PKC.…”

Section: Trpc Channelsmentioning

confidence: 99%

Control of neuronal excitability by Group I metabotropic glutamate receptors

Amb

Jds

et al. 2017

Biophys Rev

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Metabotropic glutamate (mGlu) receptors couple through G proteins to regulate a large number of cell functions. Eight mGlu receptor isoforms have been cloned and classified into three Groups based on sequence, signal transduction mechanisms and pharmacology. This review will focus on Group I mGlu receptors, comprising the isoforms mGlu 1 and mGlu 5 . Activation of these receptors initiates both G protein-dependent and -independent signal transduction pathways. The G-protein-dependent pathway involves mainly Gα q , which can activate PLCβ, leading initially to the formation of IP 3 and diacylglycerol. IP 3 can release Ca 2+ from cellular stores resulting in activation of Ca 2+ -dependent ion channels. Intracellular Ca 2+ , together with diacylglycerol, activates PKC, which has many protein targets, including ion channels. Thus, activation of the G-protein-dependent pathway affects cellular excitability though several different effectors. In parallel, G protein-independent pathways lead to activation of non-selective cationic currents and metabotropic synaptic currents and potentials. Here, we provide a survey of the membrane transport proteins responsible for these electrical effects of Group I metabotropic glutamate receptors.

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GABAB receptor activation enhances mGluR-mediated responses at cerebellar excitatory synapses

Cited by 155 publications

References 48 publications

Ca ²⁺ activity at GABA _B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

Ca ²⁺ activity at GABA _B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Control of neuronal excitability by Group I metabotropic glutamate receptors

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GABAB receptor activation enhances mGluR-mediated responses at cerebellar excitatory synapses

Cited by 155 publications

References 48 publications

Ca 2+ activity at GABA B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

Ca 2+ activity at GABA B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Control of neuronal excitability by Group I metabotropic glutamate receptors

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Product

Resources

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Ca ²⁺ activity at GABA _B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

Ca ²⁺ activity at GABA _B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA