Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons

Yonju Ha, Ying Dun, Muthusamy Thangaraju, Jennifer Duplantier, Zheng Dong, Kebin Liu, Vadivel Ganapathy, Sylvia B. Smith

Research output: Contribution to journalArticle

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Abstract

PURPOSE. To investigate the mechanism of σ receptor 1 (σR1) neuroprotection in retinal neurons. METHODS. Oxidative stress, which is implicated in diabetic retinopathy, was induced in mouse primary ganglion cells (GCs) and RGC-5 cells, and the effect of the σR1 ligand (+)-pentazocine on pro- and anti-apoptotic and endoplasmic reticulum (ER) stress gene expression was examined. Binding of σR1 to BiP, an ER chaperone protein, and σR1 phosphorylation status were examined by immunoprecipitation. Retinas were harvested from Ins2Akita/+ diabetic mice treated with (+)-pentazocine, and the expression of ER stress genes and of the retinal transcriptome was evaluated. RESULTS. Oxidative stress induced the death of primary GCs and RGC-5 cells. The effect was decreased by the application of (+)-pentazocine. Stress increased σR1 binding to BiP and enhanced σR1 phosphorylation in RGC-5 cells. BiP binding was prevented, and σR1 phosphorylation decreased in the presence of (+)-pentazocine. The ER stress proteins PERK, ATF4, ATF6, IRE1α, and CHOP were upregulated in RGC-5 cells during oxidative stress, but decreased in the presence of (+)-pentazocine. A similar phenomenon was observed in retinas of Ins2Akita/+ diabetic mice. Retinal transcriptome analysis of Ins2Akita/+ mice compared with wild-type revealed differential expression of the genes critically involved in oxidative stress, differentiation, and cell death. The expression profile of those genes was reversed when the Ins2Akita/+ mice were treated with (+)-pentazocine. CONCLUSIONS. In retinal neurons, the molecular chaperone σR1 binds BiP under stressful conditions; (+)-pentazocine may exert its effects by dissociating σR1 from BiP. As stress in retinal cells increases, phosphorylation of σR1 is increased, which is attenuated when agonists bind to the receptor.

Original languageEnglish (US)
Pages (from-to)527-540
Number of pages14
JournalInvestigative Ophthalmology and Visual Science
Volume52
Issue number1
DOIs
StatePublished - Jan 2011
Externally publishedYes

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Retinal Neurons
Pentazocine
Endoplasmic Reticulum Stress
Oxidative Stress
Phosphorylation
Transcriptome
Ganglia
Retina
Gene Expression
Molecular Chaperones
Gene Expression Profiling
Diabetic Retinopathy
Heat-Shock Proteins
sigma-1 receptor
Immunoprecipitation
Endoplasmic Reticulum
Cell Death
Ligands

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons. / Ha, Yonju; Dun, Ying; Thangaraju, Muthusamy; Duplantier, Jennifer; Dong, Zheng; Liu, Kebin; Ganapathy, Vadivel; Smith, Sylvia B.

In: Investigative Ophthalmology and Visual Science, Vol. 52, No. 1, 01.2011, p. 527-540.

Research output: Contribution to journalArticle

Ha, Y, Dun, Y, Thangaraju, M, Duplantier, J, Dong, Z, Liu, K, Ganapathy, V & Smith, SB 2011, 'Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons', Investigative Ophthalmology and Visual Science, vol. 52, no. 1, pp. 527-540. https://doi.org/10.1167/iovs.10-5731
Ha, Yonju ; Dun, Ying ; Thangaraju, Muthusamy ; Duplantier, Jennifer ; Dong, Zheng ; Liu, Kebin ; Ganapathy, Vadivel ; Smith, Sylvia B. / Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons. In: Investigative Ophthalmology and Visual Science. 2011 ; Vol. 52, No. 1. pp. 527-540.
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AU - Dun, Ying

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AU - Liu, Kebin

AU - Ganapathy, Vadivel

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N2 - PURPOSE. To investigate the mechanism of σ receptor 1 (σR1) neuroprotection in retinal neurons. METHODS. Oxidative stress, which is implicated in diabetic retinopathy, was induced in mouse primary ganglion cells (GCs) and RGC-5 cells, and the effect of the σR1 ligand (+)-pentazocine on pro- and anti-apoptotic and endoplasmic reticulum (ER) stress gene expression was examined. Binding of σR1 to BiP, an ER chaperone protein, and σR1 phosphorylation status were examined by immunoprecipitation. Retinas were harvested from Ins2Akita/+ diabetic mice treated with (+)-pentazocine, and the expression of ER stress genes and of the retinal transcriptome was evaluated. RESULTS. Oxidative stress induced the death of primary GCs and RGC-5 cells. The effect was decreased by the application of (+)-pentazocine. Stress increased σR1 binding to BiP and enhanced σR1 phosphorylation in RGC-5 cells. BiP binding was prevented, and σR1 phosphorylation decreased in the presence of (+)-pentazocine. The ER stress proteins PERK, ATF4, ATF6, IRE1α, and CHOP were upregulated in RGC-5 cells during oxidative stress, but decreased in the presence of (+)-pentazocine. A similar phenomenon was observed in retinas of Ins2Akita/+ diabetic mice. Retinal transcriptome analysis of Ins2Akita/+ mice compared with wild-type revealed differential expression of the genes critically involved in oxidative stress, differentiation, and cell death. The expression profile of those genes was reversed when the Ins2Akita/+ mice were treated with (+)-pentazocine. CONCLUSIONS. In retinal neurons, the molecular chaperone σR1 binds BiP under stressful conditions; (+)-pentazocine may exert its effects by dissociating σR1 from BiP. As stress in retinal cells increases, phosphorylation of σR1 is increased, which is attenuated when agonists bind to the receptor.

AB - PURPOSE. To investigate the mechanism of σ receptor 1 (σR1) neuroprotection in retinal neurons. METHODS. Oxidative stress, which is implicated in diabetic retinopathy, was induced in mouse primary ganglion cells (GCs) and RGC-5 cells, and the effect of the σR1 ligand (+)-pentazocine on pro- and anti-apoptotic and endoplasmic reticulum (ER) stress gene expression was examined. Binding of σR1 to BiP, an ER chaperone protein, and σR1 phosphorylation status were examined by immunoprecipitation. Retinas were harvested from Ins2Akita/+ diabetic mice treated with (+)-pentazocine, and the expression of ER stress genes and of the retinal transcriptome was evaluated. RESULTS. Oxidative stress induced the death of primary GCs and RGC-5 cells. The effect was decreased by the application of (+)-pentazocine. Stress increased σR1 binding to BiP and enhanced σR1 phosphorylation in RGC-5 cells. BiP binding was prevented, and σR1 phosphorylation decreased in the presence of (+)-pentazocine. The ER stress proteins PERK, ATF4, ATF6, IRE1α, and CHOP were upregulated in RGC-5 cells during oxidative stress, but decreased in the presence of (+)-pentazocine. A similar phenomenon was observed in retinas of Ins2Akita/+ diabetic mice. Retinal transcriptome analysis of Ins2Akita/+ mice compared with wild-type revealed differential expression of the genes critically involved in oxidative stress, differentiation, and cell death. The expression profile of those genes was reversed when the Ins2Akita/+ mice were treated with (+)-pentazocine. CONCLUSIONS. In retinal neurons, the molecular chaperone σR1 binds BiP under stressful conditions; (+)-pentazocine may exert its effects by dissociating σR1 from BiP. As stress in retinal cells increases, phosphorylation of σR1 is increased, which is attenuated when agonists bind to the receptor.

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