Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1α, mGluR2 and mGluR5, relative to neurotransmitter release sites

Luján, Rafael; Roberts, J. D. B.; Shigemoto, Ryuichi; Ohishi, Hitoshi; Somogyi, Péter

doi:10.1016/s0891-0618(97)00051-3

Cited by 374 publications

(296 citation statements)

References 95 publications

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“…A majority of postsynaptic GABA B R localize to the perisynaptic sites in central neurons including cerebellar Purkinje cells (7,48). Although there is a model (13) suggesting that the Ca o 2ϩ level in the synaptic cleft may fluctuate during synaptic transmission, such a fluctuation is unlikely to spread to the perisynaptic site (14).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…PP1␥1 and associated mGluRs are also co-localized in the same subcellular compartments of neurons in other brain areas, e.g. in hippocampal interneurons of the stratum oriens and in dendrites of cerebellar purkinje cells (7,(42)(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

“…The eight known members of this protein family are sub-divided into three groups, based on sequence homology, associated second messenger systems, and pharmacological properties (2). mGluR1 and mGluR5 (group I) stimulate phospholipase C, are selectively activated by quisqualate, and are generally expressed perisynaptically at postsynaptic sites (3)(4)(5)(6)(7). mGluR2 and mGluR3 (group II) are negatively coupled to adenylyl cyclase and do not show a specific preference for pre-or postsynaptic neurons (8 -10).…”

mentioning

confidence: 99%

Group I Metabotropic Glutamate Receptors Bind to Protein Phosphatase 1C

Croci

Sticht

Brandstätter

et al. 2003

Journal of Biological Chemistry

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The modulation of neurotransmitter receptors by kinases and phosphatases represents a key mechanism in controlling synaptic signal transduction. However, molecular determinants involved in the specific targeting and interactions of these enzymes are largely unknown. Here, we identified both catalytic ␥-isoforms of protein phosphatase 1C (PP1␥1 and PP1␥2) as binding partners of the group I metabotropic glutamate receptors type 1a, 5a, and 5b in yeast cells and pull-down assays, using recombinant and native protein preparations. The tissue distribution of interacting proteins was compared, and protein phosphatase 1C was detected in dendrites of retinal bipolar cells expressing the respective interacting glutamate receptors. We mapped interacting domains within binding partners and identified five amino acids in the intracellular C termini of the metabotropic glutamate receptors type 1a, 5a, 5b, and 7b being both necessary and sufficient to bind protein phosphatase 1C. Furthermore, we show a dose-dependent competition of these C termini in binding the enzyme. Based on our data, we investigated the structure of the identified amino acids bound to protein phosphatase 1C by homology-based molecular modeling. In summary, these results provide a molecular description of the interaction between protein phosphatase 1C and metabotropic glutamate receptors and thereby increase our understanding of glutamatergic signal transduction.The correct targeting and localization of proteins to synaptic specializations represents an important biological mechanism to regulate neuronal excitability. Increasing evidence underlines the importance of macromolecular signaling complexes, where functionally related proteins such as ion channels, neurotransmitters receptors, kinases, and phosphatases are arranged in close vicinity and are physically anchored to the synaptic cytoskeleton. Therefore, identification and characterization of interactions between synaptically localized proteins adds substantially to our understanding of molecular mechanisms of neurotransmission.Receptors for glutamate are divided in ion channel-associated (ionotropic) receptors of the AMPA-, Kainate-, and NMDAtype and in G-protein coupled (metabotropic) receptors. Although ionotropic glutamate receptors mediate fast synaptic transmission, metabotropic glutamate receptors (mGluRs) 1 modulate neuronal excitability and development, synaptic plasticity, transmitter release, and memory function using a variety of intracellular second messenger systems (1). The eight known members of this protein family are sub-divided into three groups, based on sequence homology, associated second messenger systems, and pharmacological properties (2). mGluR1 and mGluR5 (group I) stimulate phospholipase C, are selectively activated by quisqualate, and are generally expressed perisynaptically at postsynaptic sites (3-7). mGluR2 and mGluR3 (group II) are negatively coupled to adenylyl cyclase and do not show a specific preference for pre-or postsynaptic neurons (8 -10). mGluR4, mGluR7, and...

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“…Superficial ultrathin sections were collected (first 5-10 m) because immunoreactivity decreased with depth. To be able to compare the mean distribution of DGL-␣ along the plasma membrane surface of dendritic spine heads with the mean distribution of metabotropic glutamate receptor subtype 5 (mGluR5), we followed the analysis procedure of Lujan and colleagues (for details, see Lujan et al, 1996Lujan et al, , 1997. Briefly, the length of spine membrane from the edges of the synaptic junction was measured for every DGL-␣-positive spine and was divided into 60 nm bins.…”

Section: Quantitative Analysis Of the Distribution Of Dgl-␣ In The Hementioning

confidence: 99%

Molecular Composition of the Endocannabinoid System at Glutamatergic Synapses

Katona¹,

Urbán²,

Wallace³

et al. 2006

J. Neurosci.

454

452

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Endocannabinoids play central roles in retrograde signaling at a wide variety of synapses throughout the CNS. Although several molecular components of the endocannabinoid system have been identified recently, their precise location and contribution to retrograde synaptic signaling is essentially unknown. Here we show, by using two independent riboprobes, that principal cell populations of the hippocampus express high levels of diacylglycerol lipase ␣ (DGL-␣), the enzyme involved in generation of the endocannabinoid 2-arachidonoyl-glycerol (2-AG). Immunostaining with two independent antibodies against DGL-␣ revealed that this lipase was concentrated in heads of dendritic spines throughout the hippocampal formation. Furthermore, quantification of high-resolution immunoelectron microscopic data showed that this enzyme was highly compartmentalized into a wide perisynaptic annulus around the postsynaptic density of axospinous contacts but did not occur intrasynaptically. On the opposite side of the synapse, the axon terminals forming these excitatory contacts were found to be equipped with presynaptic CB 1 cannabinoid receptors. This precise anatomical positioning suggests that 2-AG produced by DGL-␣ on spine heads may be involved in retrograde synaptic signaling at glutamatergic synapses, whereas CB 1 receptors located on the afferent terminals are in an ideal position to bind 2-AG and thereby adjust presynaptic glutamate release as a function of postsynaptic activity. We propose that this molecular composition of the endocannabinoid system may be a general feature of most glutamatergic synapses throughout the brain and may contribute to homosynaptic plasticity of excitatory synapses and to heterosynaptic plasticity between excitatory and inhibitory contacts.

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Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1α, mGluR2 and mGluR5, relative to neurotransmitter release sites

Cited by 374 publications

References 95 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

Group I Metabotropic Glutamate Receptors Bind to Protein Phosphatase 1C

Molecular Composition of the Endocannabinoid System at Glutamatergic Synapses

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Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1α, mGluR2 and mGluR5, relative to neurotransmitter release sites

Cited by 374 publications

References 95 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

Group I Metabotropic Glutamate Receptors Bind to Protein Phosphatase 1C

Molecular Composition of the Endocannabinoid System at Glutamatergic Synapses

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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