An NMDA Receptor ER Retention Signal Regulated by Phosphorylation and Alternative Splicing

Scott, Derek B.; Blanpied, Thomas A.; Swanson, Geoffrey T.; Zhang, Chi; Ehlers, Michael

doi:10.1523/jneurosci.21-09-03063.2001

Cited by 387 publications

(358 citation statements)

References 62 publications

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“…In the presence of the NR2B subunit, however, the NR1-D 1 receptor complex was completely translocated to the plasma membrane. These observations are consistent with previous data showing that, when expressed alone in both heterologous cells and cultured hippocampal neurons, the NR1 subunit accumulates in the ER (19,30) due to the presence of an ER retention motif in the alternatively spliced C1 domain in its C terminus (38) and that coexpression of NR2 subunits is necessary to drive the complex to the cell membrane (19,30). Taken together, these data suggest that, in striatal medium spiny neurons, D 1 and NMDA receptors are assembled within intracellular compartments as constitutive heteromeric complexes that are delivered to functional sites.…”

Section: Discussionsupporting

confidence: 93%

Regulation of Dopamine D1 Receptor Trafficking and Desensitization by Oligomerization with Glutamate N-Methyl-D-aspartate Receptors

Fiorentini

Gardoni

Spano

et al. 2003

Journal of Biological Chemistry

206

179

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Activation of dopamine D 1 receptors is critical for the generation of glutamate-induced long-term potentiation at corticostriatal synapses. In this study, we report that, in striatal neurons, D 1 receptors are co-localized with N-methyl-D-aspartate (NMDA) receptors in the postsynaptic density and that they co-immunoprecipitate with NMDA receptor subunits from postsynaptic density preparations. Using modified bioluminescence resonance energy transfer, we demonstrate that D 1 and NMDA receptor clustering reflects the existence of direct interactions. The tagged D 1 receptor and NR1 subunit cotransfected in COS-7 cells generated a significant bioluminescence resonance energy transfer signal that was insensitive to agonist stimulation and that did not change in the presence of the NR2B subunit, suggesting that the D 1 receptor constitutively and selectively interacts with the NR1 subunit of the NMDA channel. Oligomerization with the NR1 subunit substantially modified D 1 receptor trafficking. In individually transfected HEK293 cells, NR1 was localized in the endoplasmic reticulum, whereas the D 1 receptor was targeted to the plasma membrane. In cotransfected cells, both the D 1 receptor and NR1 subunit were retained in cytoplasmic compartments. In the presence of the NR2B subunit, the NR1-D 1 receptor complex was translocated to the plasma membrane. These data suggest that D 1 and NMDA receptors are assembled within intracellular compartments as constitutive heteromeric complexes that are delivered to functional sites. Coexpression with NR1 and NR2B subunits also abolished agonist-induced D 1 receptor cytoplasmic sequestration, indicating that oligomerization with the NMDA receptor could represent a novel regulatory mechanism modulating D 1 receptor desensitization and cellular trafficking. Dopaminergic fibers originating in the substantia nigra and cortical glutamatergic neurons extensively interact in the striatum to drive the physiological functions of this structure from motor planning to reward seeking and procedural learning (1, 2). The critical importance of dopamine in this system is such that the degeneration of nigral dopaminergic neurons leads to the motor and cognitive deficits of Parkinson's disease (3).At the cellular level, nigral and cortical fibers converge on the medium spiny projection neurons (4), where dopamine D 1 -and D 2 -like receptors are coexpressed to high degree with glutamate NMDA 1 and non-NMDA receptor channels (5-8). From a functional point of view, it is well established that dopamine modulates the firing pattern of these neurons. In particular, there is evidence that dopamine, while attenuating the responses mediated by non-NMDA receptors, potentiates those associated with activation of NMDA receptors (2). The D 1 receptor appears to be involved in these interactions. In fact, activation of D 1 receptors in medium spiny neurons enhances NMDA-induced whole cell currents (2, 9) and is a critical requirement for the formation of NMDA-mediated long-term potentiation at corticostriatal...

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Section: Discussionsupporting

confidence: 93%

Regulation of Dopamine D1 Receptor Trafficking and Desensitization by Oligomerization with Glutamate N-Methyl-D-aspartate Receptors

Fiorentini

Gardoni

Spano

et al. 2003

Journal of Biological Chemistry

206

179

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“…The PSD-95 homologue SAP102 also binds to NMDA receptors and colocalizes with them at postsynaptic sites (35,45,55). In addition, SAP102 may interact with the NMDA receptor in the endoplasmic reticulum, and such an interaction may be necessary for the release of the NMDA receptor from this compartment (53,54). At variance with PSD-95, a large portion of SAP102 is effectively solubilized by Triton X-100 and coimmunoprecipitates with the immature NR1 from Triton X-100 extracts.…”

Section: Discussionmentioning

confidence: 99%

“…A reduction in the number of synapses should therefore be accompanied by a decrease in either total PSD-95 levels (caused by backlog and degradation) or the degree of its association with NMDA receptors if backlogged PSD-95 is not effectively degraded. Homologs of PSD-95 may associate with their targets in the endoplasmic reticulum (52), and such an association may be important for releasing NMDA receptor complexes from this compartment (53,54). One candidate that may fulfill this function is SAP102 (54).…”

Section: Evaluation Of Potential Changes Of Synaptic or Dendritic Strmentioning

confidence: 99%

Increased phosphorylation of the neuronal L-type Ca ²⁺ channel Ca _v 1.2 during aging

Davare

Hell

2003

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

110

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An increase in Ca 2؉ influx through L-type Ca 2؉ channels is thought to contribute to neuronal dysfunctions that underlie senile symptoms and Alzheimer's disease. The molecular basis of the agedependent up-regulation in neuronal L-type Ca 2؉ channel activity is largely unknown. We show that phosphorylation of the L-type channel Ca v1.2 by cAMP-dependent protein kinase is increased >2-fold in the hippocampus of aged rats. The hippocampus is critical for learning and is one of the first brain regions to be affected in Alzheimer's disease. Phosphorylation of Ca v1.2 by cAMP-dependent protein kinase strongly enhances its activity. Therefore, increased Ca v1.2 phosphorylation may account for a substantial portion of the age-related rise in neuronal Ca 2؉ influx and its neuropathological consequences. C a 2ϩ regulates a variety of signaling pathways (1-3). Acute uncontrolled Ca 2ϩ influx can cause neuronal death by overstimulation of the N-methyl-D-aspartate (NMDA)-type glutamate receptor (4, 5). Chronic elevation of Ca 2ϩ influx has been implicated in age-associated neuronal loss and Alzheimer's disease (6, 7). The age-related learning impairment in rabbits is reversed by the specific L-type Ca 2ϩ channel blocker nimodipine (8). These observations indicate that elevation of L-type channel activity causes neuronal dysfunction during aging. Ca 2ϩ influx through L-type channels is up-regulated Ͼ2-fold in hippocampal neurons of old versus adult rats (9). The hippocampus is crucial for learning and memory; however, the molecular basis for the increase in L-type channel activity during aging is not well defined, except for an Ϸ20% increase in Ca v 1.3 protein (10, 11). We now show that cAMP-dependent protein kinase (PKA)-mediated phosphorylation of the L-type channel Ca v 1.2 increases Ͼ2-fold during aging and that it may underlie a substantial portion of the age-related increase in L-type channel activity.PKA increases L-type channel activity in neurons (13-16) and in the heart, where PKA-dependent stimulation of the cardiac L-type channel is crucial for the up-regulation of the heartbeat after adrenergic stimulation (17, 18 (19), and the auxiliary subunits ␣ 2 -␦, -␤, and -␥ (22). Only ␣ 1 1.2, and none of the auxiliary subunits, is required for the PKA-mediated increase in channel activity (23). ␣ 1 1.2 is phosphorylated in intact hippocampal neurons by PKA (24). The main phosphorylation site on ␣ 1 1.2 is serine 1928 (25, 26), which is important for the up-regulation of the channel activity by PKA (27). This site is close to the C terminus of ␣ 1 1.2, is present only in the full-length form of ␣ 1 1.2 (21), and is removed by the Ca 2ϩ -activated protease calpain after Ca 2ϩ influx through NMDA receptors (28). Calpain cleaves ␣ 1 1.2 Ϸ300 residues upstream of the C terminus in vitro (28). Deletion of the last 300-400 residues of ␣ 1 1.2 increases channel activity when expressed in Xenopus oocytes (29); therefore, calpain-mediated cleavage may permanently elevate Ca v 1.2 activity in vivo. Because calpain has been impli...

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“…Levels of NMDA receptors in prefrontal cortex, striatum and hippocampus of wild-type and NR1-KD mice were assessed by western blot analysis, and revealed that NR2A and NR2B subunits of the NMDA receptor were also substantially reduced to approximately 10-20% as a consequence of NR1 deficiency (Figure 1). Normally the NR1 subunit is present in excess and is retained in the ER or rapidly degraded when not assembled with an NR2 subunit (Huh and Wenthold, 1999;Scott et al, 2001). In the NR1-KD mice, the NR1 subunit must be the limiting factor in the assembly of heteromeric NMDA receptors.…”

Section: Glutamate Receptor Levels In Various Brain Regions Of Nr1-kdmentioning

confidence: 99%

Genetic NMDA Receptor Deficiency Disrupts Acute and Chronic Effects of Cocaine but not Amphetamine

Ramsey

Laakso

Cyr

et al. 2008

Neuropsychopharmacol

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NMDA receptor-mediated glutamate transmission is required for several forms of neuronal plasticity. Its role in the neuronal responses to addictive drugs is an ongoing subject of investigation. We report here that the acute locomotor-stimulating effect of cocaine is absent in NMDA receptor-deficient mice (NR1-KD). In contrast, their acute responses to amphetamine and to direct dopamine receptor agonists are not significantly altered. The striking attenuation of cocaine's acute effects is not likely explained by alterations in the dopaminergic system of NR1-KD mice, since most parameters of pre-and postsynaptic dopamine function are unchanged. Consistent with the behavioral findings, cocaine induces less c-Fos expression in the striatum of these mice, while amphetamine-induced c-Fos expression is intact. Furthermore, chronic cocaine-induced sensitization and conditioned place preference are attenuated and develop more slowly in mutant animals, but amphetamine's effects are not altered significantly. Our results highlight the importance of NMDA receptor-mediated glutamatergic transmission specifically in cocaine actions, and support a hypothesis that cocaine and amphetamine elicit their effects through differential actions on signaling pathways.

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An NMDA Receptor ER Retention Signal Regulated by Phosphorylation and Alternative Splicing

Cited by 387 publications

References 62 publications

Regulation of Dopamine D1 Receptor Trafficking and Desensitization by Oligomerization with Glutamate N-Methyl-D-aspartate Receptors

Regulation of Dopamine D1 Receptor Trafficking and Desensitization by Oligomerization with Glutamate N-Methyl-D-aspartate Receptors

Increased phosphorylation of the neuronal L-type Ca ²⁺ channel Ca _v 1.2 during aging

Genetic NMDA Receptor Deficiency Disrupts Acute and Chronic Effects of Cocaine but not Amphetamine

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An NMDA Receptor ER Retention Signal Regulated by Phosphorylation and Alternative Splicing

Cited by 387 publications

References 62 publications

Regulation of Dopamine D1 Receptor Trafficking and Desensitization by Oligomerization with Glutamate N-Methyl-D-aspartate Receptors

Regulation of Dopamine D1 Receptor Trafficking and Desensitization by Oligomerization with Glutamate N-Methyl-D-aspartate Receptors

Increased phosphorylation of the neuronal L-type Ca 2+ channel Ca v 1.2 during aging

Genetic NMDA Receptor Deficiency Disrupts Acute and Chronic Effects of Cocaine but not Amphetamine

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Increased phosphorylation of the neuronal L-type Ca ²⁺ channel Ca _v 1.2 during aging