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Accueil > Agenda > Les séminaires Jean Roche > Protein interactions and the trafficking of AMPA receptors

Protein interactions and the trafficking of AMPA (...)


1 : Neuron. 2006 Jul 6 ;51(1):85-97. Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut

Developmentally regulated, combinatorial RNA processing modulates AMPA receptor biogenesis.

Greger IH, Akamine P, Khatri L, Ziff EB.

Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom. ig

The subunit composition determines AMPA receptor (AMPA-R) function and trafficking. Mechanisms underlying channel assembly are thus central to the efficacy and plasticity of glutamatergic synapses. We previously showed that RNA editing at the Q/R site of the GluR2 subunit contributes to the assembly of AMPA-R heteromers by attenuating formation of GluR2 homotetramers. Here we report that this function of the Q/R site depends on subunit contacts between adjacent ligand binding domains (LBDs). Changes of LBD interface contacts alter GluR2 assembly properties, forward traffic, and expression at synapses. Interestingly, developmentally regulated RNA editing within the LBD (at the R/G site) produces analogous effects. Our data reveal that editing to glycine reduces the self-assembly competence of this critical subunit and slows GluR2 maturation in the endoplasmic reticulum (ER). Therefore, RNA editing sites, located at strategic subunit interfaces, shape AMPA-R assembly and trafficking in a developmentally regulated manner.

PMID : 16815334 [PubMed - indexed for MEDLINE]

2 : Genome Biol. 2006 ;7(4):214. Epub 2006 Apr 27. Related Articles, Cited Articles, Books, LinkOut

Getting to synaptic complexes through systems biology.

Jordan BA, Ziff EB.

Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA.

ABSTRACT : Large numbers of synaptic components have been identified, but the effect so f ar on our understanding of synaptic function is limited. Now, network maps and annotated functions of individual components have been used in a systems biology approach to analyzing the function of NMDA receptor complexes at synapses, identifying biologically relevant modular networks within the complex.

Publication Types :

· Review

PMID : 16677427 [PubMed - indexed for MEDLINE]

3 : J Neurosci. 2006 Feb 22 ;26(8):2300-12. Related Articles, Gene, Gene (GeneRIF), HomoloGene, Nucleotide (RefSeq), Protein (RefSeq), UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut

Membrane localization of membrane type 5 matrix metalloproteinase by AMPA receptor binding protein and cleavage of cadherins.

Monea S, Jordan BA, Srivastava S, DeSouza S, Ziff EB.

Department of Biochemistry, New York University School of Medicine, New York, New York 10016, USA.

Matrix metalloproteinases (MMPs) have been proposed to remodel the extracellular environment of neurons. Here, we report that the metalloproteinase membrane-type 5 MMP (MT5-MMP) binds to AMPA receptor binding protein (ABP) and GRIP (glutamate receptor interaction protein), two related postsynaptic density (PSD) PDZ (postsynaptic density-95/Discs large/zona occludens-1) domain proteins that target AMPA receptors to synapses. The MT5-MMP C terminus binds ABP PDZ5 and the two proteins coimmunoprecipitated and colocalized in heterologous cells and neurons. MT5-MMP localized in filopodia at the tips of growth cones in young [2-5 d in vitro (DIV)] cultured embryonic hippocampal neurons, and at synapses in mature (21 DIV) neurons. Its enrichment in synaptosomes also indicated a synaptic localization in the mature brain. Deletion of the PDZ binding site impaired membrane trafficking of MT5-MMP, whereas exogenous ABP splice forms that are associated either with the plasma membrane or with the cytosol, respectively, colocalized with MT5-MMP in synaptic spines or recruited MT5-MMP to intracellular compartments. We show that endogenous MT5-MMP is found in cultured neurons and brain lysates in a proenzyme form that is activated by furin and degraded by auto-proteolysis. We also identify cadherins as MT5-MMP substrates. These results suggest that ABP directs MT5-MMP proteolytic activity to growth cones and synaptic sites in neurons, where it may regulate axon pathfinding or synapse remodeling through proteolysis of cadherins or other ECM or cell adhesion molecules.

PMID : 16495457 [PubMed - indexed for MEDLINE]

4 : Neuron. 2005 Aug 4 ;47(3):407-21. Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut

PICK1 interacts with ABP/GRIP to regulate AMPA receptor trafficking.

Lu W, Ziff EB.

Program in Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016, USA.

PICK1 and ABP/GRIP bind to the AMPA rece ptor (AMPAR) GluR2 subunit C terminus. Transfer of the receptor from ABP/GRIP to PICK1, facilitated by GluR2 S880 phosphorylation, may initiate receptor trafficking. Here we report protein interactions that regulate these steps. The PICK1 BAR domain interacts intermolecularly with the ABP/GRIP linker II region and intramolecularly with the PICK1 PDZ domain. Binding of PKCalpha or GluR2 to the PICK1 PDZ domain disrupts the intramolecular interaction and facilitates the PICK1 BAR domain association with ABP/GRIP. Interference with the PICK1-ABP/GRIP interaction impairs S880 phosphorylation of GluR2 by PKC and decreases the constitutive surface expression of GluR2, the NMDA-induced endocytosis of GluR2, and recycling of internalized GluR2. We suggest that the PICK1 interaction with ABP/GRIP is a critical step in controlling GluR2 trafficking.

PMID : 16055064 [PubMed - indexed for MEDLINE]

5 : J Biol Chem. 2004 Apr 2 ;279(14):14307-14. Epub 2004 Jan 13. Related Articles, Gene, Gene (GeneRIF), Nucleotide (RefSeq), OMIM (calculated), < a CLASS="dblinks" href="">Compound via MeSH, Substance via MeSH, Protein (RefSeq), UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut

Bidirectional regulation of neuronal nitric-oxide synthase phosphorylation at serine 847 by the N-methyl-D-aspartate receptor.

Rameau GA, Chiu LY, Ziff EB.

Howard Hughes Medical Institute, Department of Biochemistry, New York University School of Medicine, New York, New York 10016, USA.

At glutamatergic synapses, the scaffolding protein PSD95 links the neuronal isoform of nitric-oxide synthase (nNOS) to the N-methyl-d-aspartate (NMDA) receptor. Phosphorylation of nNOS at serine 847 (Ser(847)) by the calcium-calmodulin protein kinase II (CaMKII) inhibits nNOS activity, possibly by blocking the binding of Ca(2+)-CaM. Here we show that the NMDA mediates a novel bidirectional regulation of Ser(847) phosphorylation. nNOS phosphorylated at Ser(847) colocalizes with the NMDA receptor at spines of cultured hippocampal neurons. Treatment of neurons with 5 microm glutamate stimulated CaMKII phosphorylation of nNOS at Ser(847), whereas excitotoxic concentrations of glutamate, 100 and 500 microm, induced Ser(847)-PO(4) dephosphorylation by protein phosphatase 1. Strong NMDA receptor stimulation was likely to activate nNOS under these conditions because protein nitration to form nitrotyrosine, a marker of nNOS activity, correlated in individual neurons with Ser(847)-PO(4) dephosphorylation. Of particular note, stimulation with low glutamate that increased phosphorylation of nNOS at Ser(847) could be reversed by subsequent high glutamate treatment which induced dephosphorylation. The reversibility of NMDA receptor-induced phosphorylation at Ser(847) by different doses of glutamate suggests two mechanisms with opposite effects : 1). a time-dependent negative feedback induced by physiological concentrations of glutamate that limits nNOS activation and precludes the overproduction of NO ; and 2). a pathological stimulation by high concentrations of glutamate that leads to unregulated nNOS activation and production of toxic levels of NO. These mechanisms may share pathways, respectively, with NMDA receptor-induced forms of synaptic plasticity and excitotoxicity.

PMID : 14722119 [PubMed - indexed for MEDLINE]

6 : Neuron. 2003 Nov 13 ;40(4):763-74. Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut

AMPA receptor tetramerization is mediated by Q/R editing.

Greger IH, Khatri L, Kong X, Ziff EB.

Howard Hughes Medical Institute, Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA. ig

AMPA-type glutamate receptors (AMPARs) play a major role in excitatory synaptic transmission and plasticity. Channel properties are largely dictated by their composition of the four subunits, GluR1-4 (or A-D). Here we show that AMPAR assembly and subunit stoichiometry are determined by RNA editing in the pore loop. We demonstrate that editing at the GluR2 Q/R site regulates AMPAR assembly at the step of tetramerization. Specifically, edited R subunits are largely unassembled and ER retained, whereas unedited Q subunits readily tetramerize and traffic to synapses. This assembly mechanism restricts the number of the functionally critical R subunits in AMPAR tetramers. Therefore, a single amino acid residue affects channel composition and, in turn, controls ion conduction through the majority of AMPARs in the brain.

PMID : 14622580 [PubMed - indexed for MEDLINE]

7 : J Neurosci. 2003 Aug 20 ;23(20):7592-601. Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut

Intracellular membrane targeting and suppression of Ser880 phosphorylation of glutamate receptor 2 by the linker I-set II domain of AMPA receptor-binding protein.

Fu J, deSouza S, Ziff EB.

Howard Hughes Medical Institute, Department of Biochemistry, New York University School of Medicine, New York, New York 10016, USA.

AMPA receptor-binding protein (ABP) is a multi-postsynaptic density-95/discs large/zona occludens (PDZ) protein that binds to the glutamate receptor 2/3 (GluR2/3) subunits of the AMPA receptor and is implicated in receptor membrane anchorage. A palmitoylated form of ABP localizes to spine heads, whereas a nonpalmitoylated form is found in intracellular clusters. Here, we investigate intracellular cluster formation by ABP and the ability of ABP to associate with GluR2 while in these clusters. We show that ABP interacts with intracellular membranes via the ABP linker I (LI)-set II (SII) subdomain, a region consisting of ABP linker 1 and PDZ4, -5, and -6. This suggests that cluster formation results from LI-SII ABP association with the membrane of a vesicular structure. We present evidence that ABP can self-associate at intracellular membrane surfaces via interactions involving SII. ABP in such membrane clusters can bind and retain GluR2 that has trafficked endocytotically from the plasma membrane. Phosphorylation of GluR2 at serine 880, proximal to the ABP binding site, has been implicated by others in the release of ABP from GluR2 and the mobilization of AMPA receptors for trafficking. We show that binding of GluR2 to ABP blocks phosphorylation of serine 880. This suggests that ABP can stabilize its own association with GluR2. We discuss a model in which ABP can form a protein scaffold at a vesicular membrane that is capable of binding GluR2, leading to formation of an intracellular AMPA receptor pool. Receptors in such a pool may contribute to receptor endocytotic and exocytotic trafficking and recycling.

PMID : 12930798 [PubMed - indexed for MEDLINE]

8 : Sci STKE. 2002 Oct 29 ;2002(156):PE45. Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut

AMPA receptors do the electric slide.

deSouza S, Ziff EB.

Howard Hughes Medical Institute, Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA.

How the sy napse is organized and how its organization changes during events that result in long-term changes in synaptic efficacy is the subject of intense study. Various anchoring proteins work in concert to organize the postsynaptic side of the membrane, and the interactions of these proteins can be altered by synaptic activity. DeSouza and Ziff discuss the evidence that the reversible palmitoylation of the postsynaptic density protein PSD-95 may result in the movement of AMPA-type glutamate receptors into and out of lipid raft domains, ultimately controlling AMPA receptor accumulation at the postsynaptic membrane.

Publication Types :

· Review

PMID : 12407223 [PubMed - indexed for MEDLINE]

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