| First Author | Ha Y | Year | 2011 |
| Journal | Invest Ophthalmol Vis Sci | Volume | 52 |
| Issue | 1 | Pages | 527-40 |
| PubMed ID | 20811050 | Mgi Jnum | J:171562 |
| Mgi Id | MGI:4950357 | Doi | 10.1167/iovs.10-5731 |
| Citation | Ha Y, et al. (2011) Sigma receptor 1 modulates endoplasmic reticulum stress in retinal neurons. Invest Ophthalmol Vis Sci 52(1):527-40 |
| abstractText | PURPOSE: To investigate the mechanism of sigma receptor 1 (sigmaR1) 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 sigmaR1 ligand (+)-pentazocine on pro- and anti-apoptotic and endoplasmic reticulum (ER) stress gene expression was examined. Binding of sigmaR1 to BiP, an ER chaperone protein, and sigmaR1 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 sigmaR1 binding to BiP and enhanced sigmaR1 phosphorylation in RGC-5 cells. BiP binding was prevented, and sigmaR1 phosphorylation decreased in the presence of (+)-pentazocine. The ER stress proteins PERK, ATF4, ATF6, IRE1alpha, 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 sigmaR1 binds BiP under stressful conditions; (+)-pentazocine may exert its effects by dissociating sigmaR1 from BiP. As stress in retinal cells increases, phosphorylation of sigmaR1 is increased, which is attenuated when agonists bind to the receptor. |
