Interaction of the C-terminal tail region of the metabotropic glutamate receptor 7 with the protein kinase C substrate PICK1

Far, Oussama El; Airas, José M.; Wischmeyer, Erhardt; Nehring, Ralf B.; Karschin, Andreas; Betz, Heinrich

doi:10.1046/j.1460-9568.2000.01309.x

Cited by 49 publications

(81 citation statements)

References 29 publications

(48 reference statements)

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“…PKC phosphorylated Ser-881 in mGluR5, located in the PP1␥1/2 binding motifs identified in this study. PKC was also linked to mGluR7b via PICK1 (27), and PKC phosphorylation of the proximal C-terminal domain, identical between mGluR7a and mGluR7b, was shown (51).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…In particular there has been a lot of interest in PICK1 since it was originally identified as an interactor for PKCa (Staudinger et al 1995(Staudinger et al , 1997. In addition, to PKCa and GluR2, PICK1 also interacts with a number of other proteins including mGluR7 (Boudin et al 2000;Dev et al 2000;El Far et al 2000), non-voltage-gated Na 1 channels (Baron et al 2002;Duggan et al 2002;Hruska-Hageman et al 2002) and ephrin receptors (Torres et al 1998). Although PICK1 contains only a single PDZ domain, it can also dimerize via a coiled-coil domain (Perez et al 2001) providing the possibility that PICK1 dimers could target other proteins such as PKCa to AMPARs.…”

Section: The Pdz Sitementioning

confidence: 99%

GluR2 protein-protein interactions and the regulation of AMPA receptors during synaptic plasticity

Duprat

Daw

Lim

et al. 2003

Phil. Trans. R. Soc. Lond. B

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AMPA-type glutamate receptors mediate most fast excitatory synaptic transmissions in the mammalian brain. They are critically involved in the expression of long-term potentiation and long-term depression, forms of synaptic plasticity that are thought to underlie learning and memory. A number of synaptic proteins have been identified that interact with the intracellular C-termini of AMPA receptor subunits. Here, we review recent studies and present new experimental data on the roles of these interacting proteins in regulating the AMPA receptor function during basal synaptic transmission and plasticity.

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“…The intracellular C-terminal domain of the macrophage major splice variant mGluR7a interacts with several cytosolic proteins, including Ca 2ϩ -calmodulin (O'Connor et al, 1999), the protein kinase C (PKC) substrate MacMARCKS (macrophaged myristoylated alanine-rich C kinase substrate-related protein) (Bertaso et al, 2006), G-protein ␤␥ subunits, and the protein interacting with C kinase 1 (PICK1) (Dev et al, 2000;El Far et al, 2000), whereas the other known isoform, mGluR7b, binds filamin A, protein phosphatase 1C, syntenin, and PICK1 (Enz and Croci, 2003). PICK1 belongs to a large family of postsynaptic density protein-95/disc-large tumor suppressor protein/zonula occludens-1 (PDZ)-domain proteins known to be essential for diverse receptor signaling and targeting mechanisms (Dev, 2004).…”

Section: Introductionmentioning

confidence: 99%

Knock-In Mice Lacking the PDZ-Ligand Motif of mGluR7a Show Impaired PKC-Dependent Autoinhibition of Glutamate Release, Spatial Working Memory Deficits, and Increased Susceptibility to Pentylenetetrazol

Zhang

Bertaso²,

Eulenburg

et al. 2008

J. Neurosci.

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The metabotropic glutamate receptor 7 (mGluR7) is widely expressed throughout the brain and primarily localized at presynaptic active zones, where it is thought to regulate neurotransmitter release. Protein interacting with C kinase 1 (PICK1), a postsynaptic density protein-95/disc-large tumor suppressor protein/zonula occludens-1 (PDZ)-domain protein, binds to the three C-terminal amino acids (-LVI) of the predominant mGluR7 splice variant, mGluR7a, and has been implicated in the synaptic clustering of this receptor. Here, we generated knock-in mice in which the C-terminal LVI coding sequence of exon 10 of the mGluR7 gene was replaced by three alanine codons (-AAA). Immunoprecipitation showed that the PICK1-mGluR7a interaction is disrupted in mGluR7a AAA/AAA mice. However, the synaptic localization of mGluR7a was not altered in cultured hippocampal neurons and brain sections prepared from the knock-in animals. In cerebellar granule cell cultures, the group III mGluR agonist L-AP-4 decreased the frequency of spontaneous excitatory currents in neurons derived from wild-type but not mGluR7a AAA/AAA mice, consistent with the interaction between mGluR7a and PICK1 being required for protein kinase C-mediated inhibition of glutamate release. At the behavioral level, the mGluR7a AAA/AAA mice showed no deficits in motor coordination, pain sensitivity, and anxiety but exhibited significant defects in hippocampus-dependent spatial working memory. In addition, they displayed a high susceptibility to the convulsant drug pentylenetetrazole. Together, these results indicate that PICK1 binding to the C-terminal region of mGluR7a is crucial for agonist-triggered presynaptic signaling in vivo.

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Interaction of the C-terminal tail region of the metabotropic glutamate receptor 7 with the protein kinase C substrate PICK1

Cited by 49 publications

References 29 publications

Group I Metabotropic Glutamate Receptors Bind to Protein Phosphatase 1C

Group I Metabotropic Glutamate Receptors Bind to Protein Phosphatase 1C

GluR2 protein-protein interactions and the regulation of AMPA receptors during synaptic plasticity

Knock-In Mice Lacking the PDZ-Ligand Motif of mGluR7a Show Impaired PKC-Dependent Autoinhibition of Glutamate Release, Spatial Working Memory Deficits, and Increased Susceptibility to Pentylenetetrazol

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