Neuronal enriched endosomal protein of 21 kDa colocalizes with glutamate receptor subunit GLUR2/3 at the postsynaptic membrane

Utvik, Jo Kristian; Haglerød, Camilla; Mylonakou, Maria N.; Holen, Torgeir; Kropf, Michel; Hirling, Harald; Skare, Øivind; Laake, Petter; Ottersen, Ole Petter; Haug, Finn Mogens; Davanger, Svend

doi:10.1016/j.neuroscience.2008.11.030

Cited by 20 publications

(16 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The data suggested that GluR2/3 was translocated from EXTRA and intracellular LM pools to synapses initially, and then returned to the intracellular pools, probably via the endocytic pathway. 19–21 …”

Section: Resultsmentioning

confidence: 99%

Phosphorylation and Assembly of Glutamate Receptors After Brain Ischemia

Zhang

Guo

Liu

et al. 2013

Stroke

View full text Add to dashboard Cite

Background and Purpose Over-assembly of synaptic glutamate receptors leads to excitotoxicity. The goal of this study is to investigate phosphorylation and assembly of AMPA and NMDA receptors after brain ischemia with reperfusion (I/R). Methods Rats were subjected to 15 min of global ischemia followed by 0.5, 4, and 24 h of reperfusion. Phosphotyrosine (Ptyr) peptides of glutamate receptors in synaptosomal fraction after I/R were identified and quantified by state-of-the-art immuno-affinity purification of Ptyr peptides followed by LC-MS/MS analysis (IAP-LC/MS/MS). Glutamate receptor phosphorylation and synaptic assembly after I/R were studied by biochemical methods. Results Numerous Ptyr sites of AMPA and NMDA were upregulated by about 2- to 37-fold after I/R. A core glutamate receptor kinase, Src kinase, was significantly activated. GluR2/3 and NR2A/B were rapidly clustered from extrasynaptic to synaptic membrane fractions after I/R. GluR2/3 was then translocated into the intracellular pool, whereas NR2A/B remained in the synaptic fraction for as long as 24 h. Consistently, trafficking-related phosphorylation of GluR2/3-S880 was significantly but transiently upregulated, whereas NR2A/B-Y1246 and -Y1472 were significantly and persistently upregulated after I/R. Conclusions Phosphorylation of glutamate receptors at synapses may lead to over-assembly of glutamate receptors, probably via activation of Src family kinases, after I/R. This study provides “global” proteomic information about glutamate receptor tyrosine phosphorylation after brain ischemia.

show abstract

Section: Resultsmentioning

confidence: 99%

Phosphorylation and Assembly of Glutamate Receptors After Brain Ischemia

Zhang

Guo

Liu

et al. 2013

Stroke

View full text Add to dashboard Cite

show abstract

“…Second, we chose to focus our efforts on NEEP21, a protein previously shown to be present within Golgi and endosomal compartments of neurons (Sabéran-Djoneidi et al, 1998), and synaptic membranes (Utvik et al, 2009), very similar to the normal distribution of APP (Koo et al, 1990). NEEP21 has also been shown to modulate axonal trafficking and polarization of L1/NgCAM (Yap et al, 2008), is localized to endosomes in differentiated PC12 cells where it can modulate transferrin recycling as well as GluR2 recycling in neuronal cell culture (Steiner et al, 2002, 2005), and it may also play a role in AMPA receptor cycling during synaptic plasticity (Alberi et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Identification of NEEP21 as a β-Amyloid Precursor Protein-Interacting ProteinIn VivoThat Modulates Amyloidogenic ProcessingIn Vitro

Norstrom¹,

Zhang²,

Tanzi³

et al. 2010

J. Neurosci.

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is an age-related neurodegenerative disease and the most common form of dementia. AD is pathologically characterized by the deposition of pathogenic Aβ peptides that are derived from larger integral membrane proteins, termed β-amyloid precursor proteins (APPs). In an attempt to understand the function of APP, in vitro studies have focused on the identification of interacting proteins. To investigate the APP in vivo interactome in an unbiased manner, we generated mice that harbor a mouse prion protein promoter-driven cDNA encoding human APP-695 fused to a C-terminal affinity tag. Using this tag, we prepared mild detergent lysates from transgenic mouse brain cortical membrane preparations and isolated a number of previously identified APP-interacting proteins. In addition to these factors, mass spectrometric analysis revealed the presence of NEEP21 as a novel interacting protein. We now report that NEEP21 profoundly affects the processing of APP and Aβ production. Thus, this study demonstrates that using proteomic methods on our transgenic model can uncover important in vivo APP-interacting proteins that will provide insights into the biology of APP.

show abstract

“…Furthermore, NEEP21, known to regulate recycling of AMPA receptors at the synapse, has been localized by immunofluorescence inside TfR-containing endosomes of cultured hippocampal neurons (Steiner et al, 2005). However, EM observations of rat brain sections demonstrated that the protein is expressed at PSDs as well as in intralumenal, but not limiting, membranes of MVBs (Utvik et al, 2009). Thus, even if fluorescence data suggest that endosomes fusing to the plasma membrane during synaptic plasticity are recycling endosomes, one cannot yet exclude that some of these endosomes are MVBs.…”

Section: Endosomes In Neurons Control Synaptic Plasticitymentioning

confidence: 99%

Emerging Role of Neuronal Exosomes in the Central Nervous System

et al. 2012

View full text Add to dashboard Cite

Exosomes are small extracellular vesicles, which stem from endosomes fusing with the plasma membrane, and can be recaptured by receiving cells. They contain lipids, proteins, and RNAs able to modify the physiology of receiving cells. Functioning of the brain relies on intercellular communication between neural cells. These communications can modulate the strength of responses at sparse groups of specific synapses, to modulate circuits underlying associations and memory. Expression of new genes must then follow to stabilize the long-term modifications of the synaptic response. Local changes of the physiology of synapses from one neuron driven by another, have so far been explained by classical signal transduction to modulate transcription, translation, and posttranslational modifications. In vitro evidence now demonstrates that exosomes are released by neurons in a way depending on synaptic activity; these exosomes can be retaken by other neurons suggesting a novel way for inter-neuronal communication. The efficacy of inter-neuronal transfer of biochemical information allowed by exosomes would be far superior to that of direct cell-to-cell contacts or secreted soluble factors. Indeed, lipids, proteins, and RNAs contained in exosomes secreted by emitting neurons could directly modify signal transduction and protein expression in receiving cells. Exosomes could thus represent an ideal mechanism for inter-neuronal transfer of information allowing anterograde and retrograde signaling across synapses necessary for plasticity. They might also allow spreading across the nervous system of pathological proteins like PrPsc, APP fragments, phosphorylated Tau, or Alpha-synuclein.

show abstract

Neuronal enriched endosomal protein of 21 kDa colocalizes with glutamate receptor subunit GLUR2/3 at the postsynaptic membrane

Cited by 20 publications

References 31 publications

Phosphorylation and Assembly of Glutamate Receptors After Brain Ischemia

Phosphorylation and Assembly of Glutamate Receptors After Brain Ischemia

Identification of NEEP21 as a β-Amyloid Precursor Protein-Interacting ProteinIn VivoThat Modulates Amyloidogenic ProcessingIn Vitro

Emerging Role of Neuronal Exosomes in the Central Nervous System

Contact Info

Product

Resources

About