Excitotoxicity mediated by Ca2+-permeable GluR4-containing AMPA receptors involves the AP-1 transcription factor

Santos, Ana Lúcia; Duarte, Carlos B.; Iizuka, Masaki; Barsoumian, Edward L.; Ham, Jonathan; Lopes, María Celeste; Carvalho, Arsélio P.

doi:10.1038/sj.cdd.4401785

Cited by 17 publications

(22 citation statements)

References 40 publications

(60 reference statements)

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“…We last investigated whether a traumatically injured hippocampus showed an increased expression of calciumpermeable AMPARs, as these receptors contribute to progressive excitotoxic cell death and dysfunction. [6][7][8][9][10]21,22 We found during recordings from FPI rats that CA1 population spikes exhibited a naspm-induced rundown to 58.9 ± 1.7% of baseline, a significantly greater inhibition than sham animals (78.9 ± 0.79%, Po0.05, Figure 7g). However, injecting animals intravenously with TAT-QSAV (3 mg/kg) after the traumatic injury occluded naspm-induced rundown of CA1 population spike amplitude (88.2 ± 5.6%, Figure 7h).…”

Section: Resultsmentioning

confidence: 91%

PICK1-mediated GluR2 endocytosis contributes to cellular injury after neuronal trauma

Bell

Park

et al. 2009

Cell Death Differ

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Constitutive and activity-dependent regulation of the AMPA receptor GluR2 content is recognized as an important mediator of both neuronal plasticity and vulnerability to excitotoxic neuron death. In the latter case, inclusion of GluR2 protects against glutamate excitotoxicity in CNS disease by lowering receptor single-channel conductance and preventing deleterious calcium influx. We investigated the hypothesis that aberrations in GluR2 trafficking after in vitro and in vivo cerebral trauma contribute to excitotoxicity and associated calcium-dependent cell death processes. First, in an in vitro model of traumatic brain injury (TBI), we observed PICK1 and N-methyl-D-aspartic acid (NMDA) receptor-dependent phosphorylation and internalization of GluR2. The contributing cell signaling mechanisms involved enhanced binding between PKCa (the kinase that phosphorylates GluR2) and PICK1 (its PDZ-binding partner), and a novel protein interaction between PKCa and the NMDA receptor scaffolding protein PSD-95. Functionally, these phenomena enhanced single cell AMPAR mEPSCs and protracted calcium extrusion. In vivo TBI similarly promoted GluR2 phosphorylation and internalization, with enhanced expression of calcium-permeable AMPARs in the injured hippocampus. Peptide-mediated perturbation of the PKCa/PICK1 protein interaction after trauma preserved surface GluR2 expression, attenuated AMPAR-mediated toxicity, and occluded the sensitivity of neuronal physiology to calcium-permeable AMPAR antagonists. These findings suggest that experimental TBI promotes the expression of injurious GluR2-lacking AMPARs, thereby enhancing cellular vulnerability to secondary excitotoxicity. Traumatic brain injury (TBI) continues to be a leading cause of morbidity and disability in North America. 1 At the cellular level, excitotoxic stimulation of N-methyl-D-aspartate (NMDA) and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamatergic receptors has a major function in the deregulation of calcium homeostasis and acute cell swelling after TBI, ultimately leading to secondary neuronal cell death hours to days after the primary injury. 1 Unfortunately, global antagonism of these ionotropic channels (which has generally targeted the highly calciumpermeable NMDARs) is a clinically impractical approach because of interference with physiological receptor function. 2 As such, it remains of critical importance to identify novel potential intracellular targets of anti-excitotoxic therapy to mitigate delayed secondary cell loss, and improve functional outcome after TBI.Physiologically, AMPA receptors mediate the majority of excitatory ionotropic neurotransmission in the CNS. 3 Pathologically, however, AMPA receptors can also mediate excitotoxic neuronal damage when GluR2 subunits are absent from the tetrameric receptor complex 4 (composed of four subunits, GluR1-4). This is because receptors devoid of the GluR2 subunit (e.g. homomers of GluR1) exhibit two-to three-fold increases in single-channel conductance, increased calcium and zinc permeab...

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Section: Resultsmentioning

confidence: 91%

PICK1-mediated GluR2 endocytosis contributes to cellular injury after neuronal trauma

Bell

Park

et al. 2009

Cell Death Differ

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“…Although the molecular mechanisms of glutamate-induced excititoxicity are still not well understood, it is generally believed that they are Ca 21 -dependent through activation of AMPA and NMDA receptors which are considered as major players in mediating injury to oligodendrocytes in hypoxic-ischemic conditions (Deng et al, 2003;Matute et al, 2007;Salter and Fern, 2005). Increased expression of GluR3 and GluR4 has been reported to facilitate increased Ca 21 loading during excitotoxicity (Santos et al, 2006). In contrast, GluR2 has been described to have a protective role by decreasing the calcium influx.…”

Section: Discussionmentioning

confidence: 97%

Role of glutamate and its receptors and insulin‐like growth factors in hypoxia induced periventricular white matter injury

Sivakumar

Ling

et al. 2009

Glia

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This study investigated the glutamate concentration and cellular localization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid glutamate receptors (AMPA GluR2, GluR3, GluR4) along with insulin-like growth factors (IGF)-1 and -2 expression in the periventricular white matter (PWM) of neonatal rats with the aim to determine their involvement in PWM injury in hypoxia. In response to hypoxia, the PWM tissue concentration of glutamate and IGF-1 as well as mRNA and protein expression of GluR2, GluR3, GluR4, IGF-1, and -2 was upregulated. Immunoexpression of GluR2/3 and GluR4 were localized in the amoeboid microglial cells (AMC) and oligodendrocytes while that of IGF-1 and -2 were confined to AMC. In primary microglial cultures subjected to hypoxia, administration of exogenous glutamate decreased IGF-1 but increased the release of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) by the cells. Furthermore, silencing of the IGF-1 and -2 genes by RNA interference in primary microglial cultures and BV-2 cells downregulated the expression of these growth factors whereas production of glutamate, TNF-alpha, and IL-1beta in these cells was upregulated. It is suggested that increased IGF-1 and -2 expressions may be an early protective mechanism in attenuating the hypoxic damage in PWM but a subsequent glutamate-induced decrease of these growth factors may cause cellular injury due to excitotoxicity and increased production of inflammatory cytokines. In this connection, melatonin and edaravone were beneficial in enhancing IGF-1 and reducing glutamate release.

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“…39,41,105,106 Additionally, the transgenic mouse model and the overexpression of GLUA2, 3, or 4 flip isoforms in a homomeric or heteromeric receptor form have been demonstrated to induce cell death, suggesting that the increase mRNA expression of GLUA2 and 3's flip to flop ratios observed in our current study may be associated with RGC cell death induced by AMPAR stimulation following an ischemic-like injury. [107][108][109][110] Glutamate excitotoxicity has been implicated to induce apoptosis, where the excessive influx of Ca 2þ causes dysregulation of the cellular Ca 2þ homeostasis. High concentrations of intracellular Ca 2þ can further increase the production of ROS by altering the permeability transition pore of the mitochondria or activating enzymes, such as nitric oxide synthase, ultimately resulting in damage to DNA, lipids, and proteins.…”

Section: Discussionmentioning

confidence: 99%

Involvement of AMPA Receptor and Its Flip and Flop Isoforms in Retinal Ganglion Cell Death Following Oxygen/Glucose Deprivation

Park

Broyles

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The a-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors (AMPAR) subunits can be posttranscriptionally modified by alternative splicing forming flip and flop isoforms. We determined if an ischemia-like insult to retinal ganglion cells (RGCs) increases AMPAR susceptibility to s-AMPA-mediated excitotoxicity through changes in posttranscriptional modified isoforms. METHODS.Purified neonatal rat RGCs were subjected to either glucose deprivation (GD) or oxygen/glucose deprivation (OGD) conditions followed by treatment with either 100 lM s-AMPA or Kainic acid. A live-dead assay and caspase 3 assay was used to assess cell viability and apoptotic changes, respectively. We used JC-1 dye and dihydroethidium to measure mitochondria depolarization and reactive oxygen species (ROS), respectively. Calcium imaging with fura-2AM was used to determine intracellular calcium, while the fluorescentlylabeled probe, Nanoprobe1, was used to detect calcium-permeable AMPARs. Quantitative PCR (qPCR) analysis was done to determine RNA editing sites AMPAR isoforms.RESULTS. Glucose deprivation, as well as an OGD insult followed by AMPAR stimulation, produced a significant increase in RGC death. Retinal ganglion cell death was independent of caspase 3/7 activity, but was accompanied by increased mitochondrial depolarization and increased ROS production. This was associated with an elevated intracellular Ca 2þ and calcium permeable-AMPARs. The mRNA expression of GLUA2 and GLUA3 flop isoform decreased significantly, while no appreciable changes were found in the corresponding flip isoforms. There were no changes in the Q/R editing of GLUA2, while R/G editing of GLUA2 flop declined under these conditions. CONCLUSIONS. Following oxidative injury, RGCs become more susceptible to AMPAR-mediated excitotoxicity. RNA editing and changes in alternative spliced flip and flop isoforms of AMPAR subunits may contribute to increased RGC death.

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Excitotoxicity mediated by Ca2+-permeable GluR4-containing AMPA receptors involves the AP-1 transcription factor

Cited by 17 publications

References 40 publications

PICK1-mediated GluR2 endocytosis contributes to cellular injury after neuronal trauma

PICK1-mediated GluR2 endocytosis contributes to cellular injury after neuronal trauma

Role of glutamate and its receptors and insulin‐like growth factors in hypoxia induced periventricular white matter injury

Involvement of AMPA Receptor and Its Flip and Flop Isoforms in Retinal Ganglion Cell Death Following Oxygen/Glucose Deprivation

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