GluA2 Trafficking Is Involved in Apoptosis of Retinal Ganglion Cells Induced by Activation of EphB/EphrinB Reverse Signaling in a Rat Chronic Ocular Hypertension Model

Dong, Ling‐Dan; Gao, Feng; Wang, Xiaohan; Miao, Yanying; Wang, Shu-Yue; Wu, Yi; Li, Fang; Wu, Jihong; Xia, Cheng; Sun, Xinghuai; Yang, Xiong‐Li; Wang, Zhongfeng

doi:10.1523/jneurosci.4376-14.2015

Cited by 51 publications

(71 citation statements)

References 73 publications

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“…Similarly seen in our current in vitro study, different models of ocular hypertension have shown increased expression of AMPARs in RGC somas 21,116 and ectopically at the optic nerve head. 117 The application of an AMPAR antagonist or blocker was able to prevent the loss of RGCs in these models; however, it is not known if these neurons and other retina cells containing AMPARs are impaired; thus, possibly effecting vision acuity and function.…”

Section: Discussionsupporting

confidence: 88%

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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Section: Discussionsupporting

confidence: 88%

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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“…The apoptosis of RGCs is the main cause of optic nerve damage in glaucoma, and numerous factors are involved in this process [52,53] . In addition, miRNAs exist in the retina [54] , and miRNAs are expressed in the retina of eyes with advanced glaucomatous damage [55] .…”

Section: The Relationship Between Mirna and The Apoptosis Of Rgcs Caumentioning

confidence: 99%

Relationship between the Pathogenesis of Glaucoma and miRNA

Guo

Shen

et al. 2017

Ophthalmic Res

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Small RNA (microRNA or miRNA) is a kind of small noncoding single-stranded RNA that regulates complementary mRNA at the posttranscriptional level in eukaryotic organisms. As important regulatory factors, miRNAs play an important role in the occurrence and development of glaucoma and widely participate in regulating biological processes of glaucoma-related genes. This article reviews the connection between the aqueous humor, trabecular meshwork, the apoptosis of retinal ganglion cells, and miRNA.

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“…[24][25][26] For immunofluorescence double labeling, the sections were incubated with a cocktail of two primary antibodies overnight at 48C. The primary antibodies used in the present study included polyclonal goat or rabbit anti-GHSR-1a (1:50; Santa Cruz Biotechnology, Santa Cruz, CA, USA, or Sigma-Aldrich Corp., St. Louis, MO, USA), polyclonal goat anti-ghrelin (1:50), monoclonal mouse anti-Brn-3a (1:100; Santa Cruz Biotechnology), and monoclonal mouse anti-glial fibrillary acidic protein (anti-GFAP, 1:500; Sigma).…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…23,25,27 Protein samples (20 lg) were separated by using 10% or 15% SDS-PAGE. The primary antibodies included monoclonal mouse anti-b-actin (1:8000) and monoclonal mouse anti-GFAP (1:1000; Sigma), polyclonal goat anti-GHSR1a (1:1000), polyclonal goat anti-ghrelin (1:1000), polyclonal rabbit anti-phospho-Akt (1:1000), polyclonal goat anti-Akt (1:1000), polyclonal rabbit anti-mTOR (1:1000), goat anticaspase3 (1:1000; Santa Cruz Biotechnology), rabbit anti-LC3 (1:1000), rabbit anti-beclin1 (1:1000; Abcam, Cambridge, MA, USA), and rabbit anti-phospho-mTOR (1:1000; Cell Signaling Technology, Danvers, MA, USA).…”

Section: Western Blot Analysesmentioning

confidence: 99%

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Ghrelin Attenuates Retinal Neuronal Autophagy and Apoptosis in an Experimental Rat Glaucoma Model

Zhu

Zhang

Liu

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Ghrelin, a natural ligand for the growth hormone secretagogue receptor type 1a (GHSR-1a), may protect retinal neurons against glaucomatous injury. We therefore characterized the underlying mechanism of the ghrelin/GHSR-1a-mediated neuroprotection with a rat chronic intraocular hypertension (COH) model. METHODS.The rat COH model was produced by blocking episcleral veins. A combination of immunohistochemistry, Western blot, TUNEL assay, and retrograde labeling of retinal ganglion cells (RGCs) was used.RESULTS. Elevation of intraocular pressure induced a significant increase in ghrelin and GHSR1a expression in retinal cells, including RGCs and Müller cells. Western blot confirmed that the protein levels of ghrelin exhibited a transient upregulation at week 2 after surgery (G2w), while the GHSR-1a protein levels were maintained at high levels from G2w to G4w. In COH retinas, the ratio of LC3-II/LC-I and beclin1, two autophagy-related proteins, were increased from G1w to G4w, and the cleavage product of caspase3, an apoptotic executioner, was detected from G2w to G4w. Intraperitoneal injection of ghrelin significantly increased the number of surviving RGCs; inhibited the changes of LC3-II/LC-I, beclin1, and the cleavage products of caspase3; and reduced the number of TUNEL-positive cells in COH retinas. Ghrelin treatment also reversed the decreased levels of p-Akt and p-mTOR, upregulated GHSR-1a protein levels, and attenuated glial fibrillary acidic protein levels in COH retinas.CONCLUSIONS. All these results suggest that ghrelin may provide neuroprotective effect in COH retinas through activating ghrelin/GHSR-1a system, which was mediated by inhibiting retinal autophagy, ganglion cell apoptosis, and Müller cell gliosis.

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GluA2 Trafficking Is Involved in Apoptosis of Retinal Ganglion Cells Induced by Activation of EphB/EphrinB Reverse Signaling in a Rat Chronic Ocular Hypertension Model

Cited by 51 publications

References 73 publications

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

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

Relationship between the Pathogenesis of Glaucoma and miRNA

Ghrelin Attenuates Retinal Neuronal Autophagy and Apoptosis in an Experimental Rat Glaucoma Model

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