Activity-Dependent mRNA Splicing Controls ER Export and Synaptic Delivery of NMDA Receptors

Mu, Yuanyue; Ôtsuka, Takeshi; Horton, April C.; Scott, Derek B.; Ehlers, Michael

doi:10.1016/s0896-6273(03)00676-7

Cited by 224 publications

(179 citation statements)

References 51 publications

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“…Whereas neuronal activity down-regulates synaptic NMDAreceptor subunit density and channel function, biochemical studies show that total neuronal NR1 levels are unchanged (3,4). These reports (3,4) imply that activity disperses NMDA receptors away from synapses. We find that augmenting neuronal activity in the presence of dominant-negative Fbx2 increases extrasynaptic NMDA-receptor density.…”

Section: Discussionmentioning

confidence: 96%

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Activity-dependent NMDA receptor degradation mediated by retrotranslocation and ubiquitination

Kato

Rouach

Nicoll

et al. 2005

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

140

100

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The extracellular N-terminal domain (NTD) is the largest region of NMDA receptors; however, biological roles for this ectodomain remain unknown. Here, we determined that the F-box protein, Fbx2, bound to high-mannose glycans of the NR1 ectodomain. F-box proteins specify ubiquitination by linking protein substrates to the terminal E3 ligase. Indeed, ubiquitination of NR1 was increased by Fbx2 and diminished by an Fbx2 dominant-negative mutant. When expressed in hippocampal neurons, this Fbx2 dominant-negative mutant augmented NR1 subunit levels and NMDA receptor-mediated currents in an activity-dependent fashion. These results suggest that homeostatic control of synaptic NR1 involves receptor retrotranslocation and degradation by the ubiquitin-proteasome pathway.endoplasmic reticulum degradation pathway ͉ neuronal activity ͉ NFB42 ͉ proteasome ͉ ubiquitylation

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Section: Discussionmentioning

confidence: 96%

“…Therefore, neurons must precisely control NMDA-receptor levels. Indeed, global neuronal activity negatively regulates the density of synaptic NMDA receptors (1)(2)(3)(4).…”

Section: N -Methyl-d-aspartate (Nmda)-type Glutamate Receptorsmentioning

confidence: 99%

Activity-dependent NMDA receptor degradation mediated by retrotranslocation and ubiquitination

Kato

Rouach

Nicoll

et al. 2005

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

140

100

View full text Add to dashboard Cite

show abstract

“…Inhibition of CaMK IV also leads to neuron death in cell cultures [207], and CaMK IV deficiency in mice results in loss of learning or memory or in less drug tolerance [208][209][210][211]. The ion channels involved in Ca ++ toxicity including the AMPA and NMDA receptors undergo alternative splicing [202,204], and inclusion of the NMDAR1 exons 5 and 21 is controlled by membrane depolarization and CaMK IV [84,104,105,107,212]. In addition, the ICH-1S variant induced by thapsigargin or ischemia prevents cell death [213,214].…”

Section: Neuronal Death and Neurodegenerative Diseasesmentioning

confidence: 99%

Control of alternative pre-mRNA splicing by Ca++ signals

Xie¹

2008

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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Alternative pre-mRNA splicing is a common way of gene expression regulation in metazoans. The selective use of specific exons can be modulated in response to various manipulations that alter Ca ++ signals, particularly in neurons. A number of splicing factors have also been found to be controlled by Ca ++ signals. Moreover, pre-mRNA elements have been identified that are essential and sufficient to mediate Ca ++ -regulated splicing, providing model systems for dissecting the involved molecular components. In neurons, this regulation likely contributes to the fine-tuning of neuronal properties.

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“…3 Alternative splicing of the C2 cassette regulates cellular trafficking and cell surface expression of the NMDA receptor. [14][15][16] NMDA receptors are predominantly expressed in the postsynaptic membrane where they interact with an intracellularly organized multiprotein complex termed the postsynaptic density (PSD). 17,18 Proteins of the membrane-associated guanylate-kinase family (MAGUKs), a group of PSD-associated proteins characterized by the presence of guanylate kinase, PDZ and Src homology 3 (SH3) protein-interacting domains, function as scaffolding and organizer proteins of the PSD.…”

Section: Introductionmentioning

confidence: 99%

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

et al. 2006

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Abnormal expression of the N-Methyl-D-Aspartate (NMDA) receptor and its interacting molecules of the postsynaptic density (PSD) are thought to be involved in the pathophysiology of schizophrenia. Frontal regions of neocortex including dorsolateral prefrontal (DLPFC) and anterior cingulate cortex (ACC) are essential for cognitive and behavioral functions that are affected in schizophrenia. In this study, we have measured protein expression of two alternatively spliced isoforms of the NR1 subunit (NR1 C2 and NR1 C2 0 ) as well as expression of the NR2A-D subunits of the NMDA receptor in DLPFC and ACC in post-mortem samples from elderly schizophrenic patients and a comparison group. We found significantly increased expression of NR1 C2 0 but not of NR1 C2 in ACC, suggesting altered NMDA receptor cell membrane expression in this cortical area. We did not find significant changes in the expression of either of the NR1 isoforms in DLPFC. We did not detect changes of any of the NR2 subunits studied in either cortical area. In addition, we studied expression of the NMDAinteracting PSD molecules NF-L, SAP102, PSD-95 and PSD-93 in ACC and DLPFC at both transcriptional and translational levels. We found significant changes in the expression of NF-L in DLPFC, and PSD-95 and PSD-93 in ACC; increased transcript expression was associated with decreased protein expression, suggesting abnormal translation and/or accelerated protein degradation of these molecules in schizophrenia. Our findings suggest abnormal regional processing of the NMDA receptor and its associated PSD molecules, possibly involving transcription, translation, trafficking and protein stability in cortical areas in schizophrenia.

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Activity-Dependent mRNA Splicing Controls ER Export and Synaptic Delivery of NMDA Receptors

Cited by 224 publications

References 51 publications

Activity-dependent NMDA receptor degradation mediated by retrotranslocation and ubiquitination

Activity-dependent NMDA receptor degradation mediated by retrotranslocation and ubiquitination

Control of alternative pre-mRNA splicing by Ca++ signals

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

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