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Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons.

ABSTRACT: PURPOSE:To investigate the mechanism of ? receptor 1 (?R1) 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 ?R1 ligand (+)-pentazocine on pro- and anti-apoptotic and endoplasmic reticulum (ER) stress gene expression was examined. Binding of ?R1 to BiP, an ER chaperone protein, and ?R1 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 ?R1 binding to BiP and enhanced ?R1 phosphorylation in RGC-5 cells. BiP binding was prevented, and ?R1 phosphorylation decreased in the presence of (+)-pentazocine. The ER stress proteins PERK, ATF4, ATF6, IRE1?, 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 ?R1 binds BiP under stressful conditions; (+)-pentazocine may exert its effects by dissociating ?R1 from BiP. As stress in retinal cells increases, phosphorylation of ?R1 is increased, which is attenuated when agonists bind to the receptor.

SUBMITTER: Ha Y

PROVIDER: S-EPMC3053296 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons.

Ha Yonju Y Dun Ying Y Thangaraju Muthusamy M Duplantier Jennifer J Dong Zheng Z Liu Kebin K Ganapathy Vadivel V Smith Sylvia B SB

Investigative ophthalmology & visual science 20110125 1

<h4>Purpose</h4>To investigate the mechanism of σ receptor 1 (σR1) neuroprotection in retinal neurons.<h4>Methods</h4>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 immunoprecip ...[more]

PMID: 20811050

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Project description:The prevalence of diabetes-associated cognitive dysfunction (DACD) has increased to 13.5%. Dementia, as the most severe DACD, is the second leading cause of death in patients with diabetes mellitus. Hence, the potential mechanisms of DACD for slowing or halting its progression need to be urgently explored. Given that the sigma-1 receptor (Sig-1R), a chaperone protein located in the endoplasmic reticulum (ER)-mitochondrion contact membranes to regulate ER stress (ERS), is associated with cognitive outcomes in neurodegenerative diseases, this study aimed to investigate the role of astrocytic Sig-1R in DACD and its underlying mechanism. Here, we examined the levels of ERS and complement component 3/3a (C3/C3a) from primary astrocytes with different concentrations of glucose and treatment. Subsequently, HT22 neurons were cultured in different astrocyte-conditioned medium, and the expression of synaptic proteins was detected. We constructed type 1 diabetes mellitus (T1DM) model to evaluate the astrocytic Sig-1R mechanism on synapse and cognitive function changes. In vitro, high glucose concentration downregulated Sig-1R and aggravated ERS in astrocytes, resulting in synapse deficits. PRE-084, a high-affinity and selective Sig-1R agonist, inhibited astrocytic ERS and complement cascades and restored synaptic damage, while the Sig-1R antagonist displayed the opposite results. Moreover, C3a receptor antagonist (C3aRA) could mimic the effect of PRE-084 and exerted neuroprotective effects. In vivo, PRE-084 substantially reduced ER-mitochondrion contact, activation of ERS, and C3/C3a secretion in mice with T1DM. Additionally, the synaptic loss and neurobehavioral dysfunction of mice with T1DM were less pronounced in both the PRE-084 and C3aRA treatment groups. These findings demonstrated that Sig-1R activation reduced the astrocytic ER-mitochondrion contact, ERS activation, and complement-mediated synaptic damage in T1DM. This study suggested the mechanisms and potential therapeutic approaches for treating DACD.

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Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons.

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Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons.

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