Ampa receptor mediated excitotoxicity in neocortical neurons is developmentally regulated and dependent upon receptor desensitization

Jensen, Jette B.; Schousboe, Arne; Pickering, Darryl S.

doi:10.1016/s0197-0186(97)00130-7

Cited by 45 publications

(47 citation statements)

References 45 publications

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“…Based on previous reports, we focused on the GluR1/2 AMPA receptor combination, one of the two most common AMPA receptor subunit combinations in the hippocampus, and, in addition, these subunits have important defined roles in AMPA receptor trafficking and synaptic plasticity (Wenthold et al, 1996). AMPA receptor-mediated excitotoxicity was induced by incubation with 30 M AMPA and 25 M cyclothiazide (this was used to prevent AMPA receptors desensitization) for 24 h as described previously (Brorson et al, 1995;Jensen et al, 1998). Apoptotic cells were detected using the ApoAlert MitoSensor kit (Clontech) as described previously (Lee et al, 2002a).…”

Section: Activation Of D 2 Receptor Inhibits Ampa Receptor-mediated Ementioning

confidence: 99%

Protein-Protein Coupling/Uncoupling Enables Dopamine D₂Receptor Regulation of AMPA Receptor-Mediated Excitotoxicity

Zou

Li²,

Lin³

et al. 2005

J. Neurosci.

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There is considerable evidence that dopamine D 2 receptors can modulate AMPA receptor-mediated neurotoxicity. However, the molecular mechanism underlying this process remains essentially unclear. Here we report that D 2 receptors inhibit AMPA-mediated neurotoxicity through two pathways: the activation of phosphoinositide-3 kinase (PI-3K) and downregulation of AMPA receptor plasma membrane expression, both involving a series of protein-protein coupling/uncoupling events. Agonist stimulation of D 2 receptors promotes the formation of the direct protein-protein interaction between the third intracellular loop of the D 2 receptor and the ATPase N-ethylmaleimide-sensitive factor (NSF) while uncoupling the NSF interaction with the carboxyl tail (CT) of the glutamate receptor GluR2 subunit of AMPA receptors. Previous studies have shown that full-length NSF directly couples to the GluR2 CT and facilitates AMPA receptor plasma membrane expression. Furthermore, the CT region of GluR2 subunit is also responsible for several other intracellular protein couplings, including p85 subunit of PI-3K. Therefore, the direct coupling of D 2 -NSF and concomitant decrease in the NSF-GluR2 interaction results in a decrease of AMPA receptor membrane expression and an increase in the interaction between GluR2 and the p85 and subsequent activation of PI-3K. Disruption of the D 2 -NSF interaction abolished the ability of D 2 receptor to attenuate AMPAmediated neurotoxicity by blocking the D 2 activation-induced changes in PI-3K activity and AMPA receptor plasma membrane expression. Furthermore, the D 2 -NSF-GluR2-p85 interactions are also responsible for the D 2 inhibition of ischemia-induced cell death. These data may provide a new avenue to identify specific targets for therapeutics to modulate glutamate receptor-governed diseases, such as stroke.

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Section: Activation Of D 2 Receptor Inhibits Ampa Receptor-mediated Ementioning

confidence: 99%

Protein-Protein Coupling/Uncoupling Enables Dopamine D₂Receptor Regulation of AMPA Receptor-Mediated Excitotoxicity

Zou

Li²,

Lin³

et al. 2005

J. Neurosci.

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“…The KA/AMPA receptor antagonist CNQX (Bleakman and Lodge, 1998), the AMPA receptor antagonist GYKI 52466 (Jensen et al, 1998;Bleakman and Lodge, 1998), and the NMDA receptor antagonist MK-801 (Regan et al, 1995) were employed to elucidate the excitotoxic profile of KA, IW, ATPA, and 4MG. Preliminary studies established that 20 M GYKI 52466 significantly protected against AMPA (1-1,000 M)-induced neurotoxicity (F 1,13 ϭ 4.82, P ϭ 0.007; cf.…”

Section: Cell Viabilitymentioning

confidence: 99%

“…Ionotropic glutamate receptors of the non-NMDA subtypes are known to have roles in neuronal injury (Frandsen et al, 1989;Koh et al, 1990;Jensen et al, 1998;John et al, 1999), with KA receptor subtypes being of historical importance in defining the initial phenomenon of excitotoxicity (Coyle, 1983). Although early studies demonstrated the existence of two [ 3 H]KA binding sites in rat forebrain membranes (London and Coyle, 1979), more recent molecular biological studies have established that there exist high-affinity (KA1-2) and low-affinity (GluR5-7) KA receptor subtypes (Chittajallu et al, 1999), the latter sites recently having been mapped in primate brain (Carroll et al, 1998).…”

mentioning

confidence: 99%

Low-affinity kainate receptor agonists induce insult-dependent apoptosis and necrosis in cultured murine cortical neurons

et al. 2000

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Overstimulation of ionotropic glutamate receptors leads to excitotoxic neuronal death, which has been implicated in the neurodegeneration of neurological diseases. The present study examined the role of putative low-affinity kainate receptor subtype (GluR5-7) agonists in excitotoxicity in cultured murine cortical neurons. The concentration-dependent decrease in cell viability induced by the agonists kainate (1-1,000 microM) and (RS)-2-amino-3-(hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA; 1-1,000 microM) was only attenuated by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 10 microM) and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466; 20 microM). (S)-5-iodowillardiine (1-1,000 microM)-induced toxicity was attenuated by CNQX (20 microM), GYKI 52466 (20 microM) and MK-801 (10 microM); however, (2S, 4R)-4-methylglutamate (1-120 microM)-induced toxicity was not attenuated by the antagonists. None of the agonists possessed selective actions at GluR5-7. Morphological observations (phase-contrast and fluorescence microscopy) revealed that the agonists induced two distinct patterns of neuronal injury. After 24 hr of treatment, low concentrations of agonists (1-30 microM) produced cellular shrinkage and nuclear granulation consistent with slow, apoptotic-like neuronal death. Pyknotic labeling with the DNA binding dye Sytox green confirmed these apoptotic characteristics, which significantly decreased with increasing concentrations. After 4 hr, increasing concentrations of agonists (100-1,000 microM) induced cellular swelling, with subsequent extracellular debris; labeling with propidium iodide revealed isolated nuclei consistent with the increased involvement of rapid necrosis. Thus, all putative GluR5-7 agonists produced excitotoxicity across a necrotic-apoptotic continuum in murine cortical neuron cultures.

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“…Most likely, this is a consequence of a high Ca 2ϩ influx through Ca 2ϩ -permeable, non-NMDA receptor channels and, subsequently, an increase in [Ca 2ϩ ] i that leads to cell death (Lu et al, 1996). Recently, it was shown that AMPA receptor-mediated toxicity in cultured murine neocortical neurons increases during development and is highly dependent on receptor desensitization (Jensen et al, 1998). To determine whether any correlation exists between the presence of Ca 2ϩ -permeable AMPA receptor channels during development and the increase in AMPA receptor mediated toxicity, the present developmental study of cobalt uptake into these neurons was performed.…”

Section: Introductionmentioning

confidence: 99%

Development of calcium-permeable ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in cultured neocortical neurons visualized by cobalt staining

Jensen¹,

Schousboe²,

Pickering³

1998

J. Neurosci. Res.

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The developmental expression of calcium (Ca2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in cultured neocortical neurons was evaluated by using cobalt uptake, a histochemical method that identifies cells expressing Ca2+-permeable, non-N-methyl-D-aspartate (non-NMDA) receptors. At a concentration of 500 microM, AMPA was found to stimulate cobalt uptake only late in development, resulting in staining of 2.7%+/-0.3% of the neurons maintained in culture for 12 days in vitro (DIV). When AMPA receptor desensitization was blocked with 50 microM cyclothiazide, the developmental profile of cobalt uptake mediated by 25 microM AMPA changed dramatically. The cobalt staining now appeared in young cultures (5 DIV), and the percentage of stained cells increased from 3.4%+/-0.2% at 5 DIV to 21.7%+/-1.6% at 12 DIV. The effect of 200 microM kainate was similar to that seen with 25 microM AMPA plus 50 microM cyclothiazide, resulting in 17.7%+/-0.3% stained neurons at 12 DIV. The cobalt uptake was specific to AMPA and kainate receptors because NMDA receptors and voltage-gated calcium channels were found not to mediate any cobalt staining. In addition, 10 microM 6-nitro-7-sulphamoylbenzo-[f]-quinoxaline-2,3-dione (NBQX) was able to prevent all staining at 5 and 8 DIV and most of the staining at 12 DIV, indicating that the non-NMDA ionotropic glutamate receptors are involved in cobalt uptake into the neurons. The AMPA receptor-selective antagonist GYKI 53655 was used to differentiate between cobalt influx through AMPA- or kainate-preferring receptors. After pretreatment with concanavalin A (con A), an inhibitor of kainate receptor desensitization, cobalt uptake was assessed after stimulation by 200 microM kainate in the presence of 25 microM GYKI 53655. No cobalt staining was observed under these conditions, indicating that most if not all of the cobalt influx induced by kainate was mediated through AMPA receptor channels.

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Ampa receptor mediated excitotoxicity in neocortical neurons is developmentally regulated and dependent upon receptor desensitization

Cited by 45 publications

References 45 publications

Protein-Protein Coupling/Uncoupling Enables Dopamine D₂Receptor Regulation of AMPA Receptor-Mediated Excitotoxicity

Protein-Protein Coupling/Uncoupling Enables Dopamine D₂Receptor Regulation of AMPA Receptor-Mediated Excitotoxicity

Low-affinity kainate receptor agonists induce insult-dependent apoptosis and necrosis in cultured murine cortical neurons

Development of calcium-permeable ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in cultured neocortical neurons visualized by cobalt staining

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Ampa receptor mediated excitotoxicity in neocortical neurons is developmentally regulated and dependent upon receptor desensitization

Cited by 45 publications

References 45 publications

Protein-Protein Coupling/Uncoupling Enables Dopamine D2Receptor Regulation of AMPA Receptor-Mediated Excitotoxicity

Protein-Protein Coupling/Uncoupling Enables Dopamine D2Receptor Regulation of AMPA Receptor-Mediated Excitotoxicity

Low-affinity kainate receptor agonists induce insult-dependent apoptosis and necrosis in cultured murine cortical neurons

Development of calcium-permeable ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in cultured neocortical neurons visualized by cobalt staining

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Protein-Protein Coupling/Uncoupling Enables Dopamine D₂Receptor Regulation of AMPA Receptor-Mediated Excitotoxicity

Protein-Protein Coupling/Uncoupling Enables Dopamine D₂Receptor Regulation of AMPA Receptor-Mediated Excitotoxicity