Expression of N-methyl-D-aspartate receptors using vaccinia virus causes excitotoxic death in human kidney cells

Garcı́a-Gallo, Mónica; Behrens, M. Margarita; Renart, Jaime; Dı́az-Guerra, Margarita

doi:10.1002/(sici)1097-4644(19990101)72:1<135::aid-jcb14>3.0.co;2-m

Cited by 7 publications

(15 citation statements)

References 40 publications

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“…However, in rat tissue and cotransfected cells, D1 and NMDA receptors could associate without exogenous NMDA receptor agonist stimulation. It is possible that constitutive NMDA receptor activation may occur because of glutamate found in the growth media (Garcia-Gallo et al, 1999).…”

Section: Nmda Receptor Nr1 Subunit Directly Couples To Dopamine D1 Rementioning

confidence: 99%

Regulation of Dopamine D1 Receptor Function by Physical Interaction with the NMDA Receptors

Lin¹,

Lee²,

Moszczynska³

et al. 2004

J. Neurosci.

179

142

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Functional interactions between dopamine D1-like receptors and NMDA subtype glutamate receptors have been implicated in the maintenance of normal brain activity and neurological dysfunction. Although modulation of NMDA receptor functions by D1 receptor activation has been the subject of extensive investigation, little is known as to how the activation of NMDA receptors alters D1 function. Here we report that NMDA receptors regulate D1 receptor function via a direct protein-protein interaction mediated by the carboxyl tail regions of both receptors. In both cotransfected cells and cultured hippocampal neurons the activation of NMDA receptors increases the number of D1 receptors on the plasma membrane surface and enhances D1 receptor-mediated cAMP accumulation via a SNAREdependent mechanism. Furthermore, overexpression of mini-genes encoding either NR1 or D1 carboxyl tail fragments disrupts the D1-NR1 direct protein-protein interaction and abolishes NMDA-induced changes in both D1 cell surface expression and D1-mediated cAMP accumulation. Our results demonstrate that the D1-NR1 physical interaction enables NMDA receptors to increase plasma membrane insertion of D1 receptors and provides a novel mechanism by which the activation of NMDA receptors upregulates D1 receptor function. Understanding the molecular mechanisms by which D1 and NMDA receptors functionally interact may provide insight toward elucidating the molecular neurobiological mechanisms involved in many neuropsychiatric illnesses, such as schizophrenia.

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Section: Nmda Receptor Nr1 Subunit Directly Couples To Dopamine D1 Rementioning

confidence: 99%

Regulation of Dopamine D1 Receptor Function by Physical Interaction with the NMDA Receptors

Lin¹,

Lee²,

Moszczynska³

et al. 2004

J. Neurosci.

179

142

View full text Add to dashboard Cite

show abstract

“…, 1990; Anegawa et al. , 1995; García‐Gallo et al. , 1999) or evidence of NMDA receptor activation by excitatory amino acids originating from culture medium (e.g.…”

Section: Mechanisms By Which Ampa Produces Ampa Receptor Internalizatmentioning

confidence: 99%

“…We propose that AMPA depolarizes NAc neurons, thereby relieving Mg 2+ block and enabling NMDA receptor activation by endogenous glutamate or aspartate originating from the culture medium. Other groups have found significant amounts of glutamate or aspartate in culture medium (Schramm et al, 1990;Anegawa et al, 1995;García-Gallo et al, 1999) or evidence of NMDA receptor activation by excitatory amino acids originating from culture medium (e.g. Boeckman & Aizenman, 1996;Raymond et al, 1996).…”

Section: Mechanisms By Which Ampa Produces Ampa Receptor Internalizatmentioning

confidence: 99%

Stimulation of N‐methyl‐d‐aspartate receptors, AMPA receptors or metabotropic glutamate receptors leads to rapid internalization of AMPA receptors in cultured nucleus accumbens neurons

Mangiavacchi

Wolf

2004

Eur J of Neuroscience

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In hippocampus and other regions, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors are inserted into synapses during long-term potentiation and removed during long-term depression. However, little is known about regulation of AMPA receptor trafficking in the nucleus accumbens (NAc), despite growing evidence that glutamate-dependent forms of plasticity in the NAc contribute to drug addiction. Using postnatal rat NAc cultures and an immunocytochemical method that selectively detects newly internalized GluR1, we studied the regulation of AMPA receptor internalization in NAc neurons by glutamate agonists. Newly internalized GluR1 was detected during 15 or 30 min of incubation at room temperature, indicating a basal rate of GluR1 turnover. The rate of GluR1 internalization was increased by glutamate (50 microM) within 5 min of its addition. Glutamate-induced GluR1 internalization was partially blocked by either an AMPA receptor antagonist (CNQX; 20 microM) or an N-methyl-D-aspartate (NMDA) receptor antagonist (APV; 50 microM). Both NMDA (50 microM) and AMPA (50 microM) increased GluR1 internalization in a Ca(2+)-dependent manner. The NMDA effect was blocked by APV while the AMPA effect was blocked by APV or CNQX. We interpret these findings to suggest that NMDA and AMPA ultimately trigger GluR1 internalization through the same NMDA receptor-dependent pathway. The effect of glutamate was also partially blocked by the group 1 metabotropic glutamate receptor antagonist N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC; 50 microM), while the group 1 agonist 3,5-dihydroxyphenylglycine (DHPG; 50 microM) stimulated GluR1 internalization. These data suggest that AMPA receptors on NAc neurons may be subject to rapid regulation of their surface expression in response to changes in the activity of glutamate inputs from cortical and limbic regions.

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“…HEK293 cells (3 × 10 6 , in six‐well plates) were infected with vTF7‐3 virus at a multiplicity of 4 plaque forming units (pfu) per cell for 1 hr at 37°C. After adsorption, virus inoculum was removed, and cells were washed once with DMEM with no serum and transfected using Transfectace liposomes as described elsewhere (Garcia‐Gallo et al,1999). Transfection of NR1 and NR2A cDNAs was performed with 4 μg each plasmid.…”

Section: Methodsmentioning

confidence: 99%

“…A well‐established feature is the different trafficking of NR1 and NR2 subunits. Approximately 50–60% of NR1 does not reach the cell surface (Hall and Soderling,1997) and constitutes an intracellular pool of immature protein of very short half‐life compared with NR2A‐assembled NR1 reaching the cell surface (Chazot and Stephenson,1997; Garcia‐Gallo et al,1999; Huh and Wenthold,1999).…”

mentioning

confidence: 99%

Endoplasmic reticulum‐associated degradation of the NR1 but not the NR2 subunits of the N‐methyl‐D‐aspartate receptor induced by inhibition of the N‐glycosylation in cortical neurons

Gascón

Garcı́a-Gallo

Renart

et al. 2007

J of Neuroscience Research

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The N-methyl-D-aspartate receptor (NMDAR) is fundamental to normal and pathological functioning of neurons. The receptor subunits are N-glycosylated proteins synthesized in the endoplasmic reticulum (ER) that fold, mature, and oligomerize as they transit through the secretory pathway. Although the early processes of biogenesis are fundamental to NMDAR expression and function, our knowledge of them is nevertheless limited. Additionally, the investigation of NMDAR synthesis is highly relevant, in that ER dysfunction, frequently associated with acute and degenerative brain diseases, might alter this process. We characterize here the effect of ER stress produced by inhibition of N-glycosylation on NMDAR synthesis and function. We use first heterologous systems of NMDAR expression in which NR1 and NR2A subunits are synthesized in nonneuronal cells. The function of these NMDARs as Ca2+ channels is repressed by tunicamycin, because of the inhibition of NR1, but no NR2A, synthesis. The regulation of NR1 is relevant to the central nervous system, in that a dramatic decrease in synthesis of this subunit and assembly of NMDARs is observed in cortical neurons treated with tunicamycin. The inhibition of NR1 synthesis is not due to changes in levels of mRNA but associated with the earliest stages in NMDAR biogenesis. The inhibition of N-glycosylation activates ER-specific stress responses in neurons, which include the ER-associated degradation (ERAD) mechanism responsible for differential and extremely efficient degradation of nonglycosylated NR1 by the proteasome after ubiquitination. Because this is an obligatory NMDAR component, the significant sensitivity of NR1 to ER stress will have important consequences on receptor function.

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Expression of N-methyl-D-aspartate receptors using vaccinia virus causes excitotoxic death in human kidney cells

Cited by 7 publications

References 40 publications

Regulation of Dopamine D1 Receptor Function by Physical Interaction with the NMDA Receptors

Regulation of Dopamine D1 Receptor Function by Physical Interaction with the NMDA Receptors

Stimulation of N‐methyl‐d‐aspartate receptors, AMPA receptors or metabotropic glutamate receptors leads to rapid internalization of AMPA receptors in cultured nucleus accumbens neurons

Endoplasmic reticulum‐associated degradation of the NR1 but not the NR2 subunits of the N‐methyl‐D‐aspartate receptor induced by inhibition of the N‐glycosylation in cortical neurons

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