Sigma receptor 1 modulates ER stress and Bcl2 in murine retina

Abstract

Sigma receptor 1 (σR1), a non-opiate transmembrane protein located on endoplasmic reticulum (ER) and mitochondrial membranes, is considered a molecular chaperone. Marked protection against cell death has been observed when ligands for σR1 have been used in in vitro and in vivo models of retinal cell death. Mice lacking σR1 (σR1−/−) manifest late onset loss of retinal ganglion cells and retinal electrophysiological changes (after many months). The role of σR1 in retina and the mechanisms by which its ligands afford neuroprotection are unclear. To explore this we used σR1−/− mice and investigated expression of ER stress genes (BiP/GRP78, Atf6, Atf4, Ire1α) and proteins involved in apoptosis (BCL2, BAX) and examined the retinal transcriptome at young ages. While there were no significant changes in expression of major ER stress genes (over a period of a year) in neural retina, there were marked changes in these genes especially Atf6 in isolated retinal Müller glial cells. BCL2 levels decreased in σR1−/− retina concomitant with decreases in NFkB and pERK1/2. We postulate that σR1 regulates ER stress in retinal Müller cells and that the role of σR1 in retinal neuroprotection likely involves BCL2 and some of the proteins that modify its expression (such as ERK, NFκB). Data from the analysis of the retinal transcriptome of σR1 null mice provides new avenues to understand the role of σR1 in retinal neuroprotection.

Sigma 1 receptor regulates the oxidative stress response in primary retinal Müller glial cells via NRF2 signaling and system xc−, the Na+-independent glutamate–cystine exchanger

“…Regarding expression of Gpx2 and Gpx3, these are both members of the glutathione peroxidase (GPx) family of enzymes, which catalyze the reduction of hydrogen peroxide to water (or alcohol) typically using GSH as the reductant. In our previous microarray analysis of the σ1RKO neural retina [20] we observed a significant increase in Gpx3 in retinas of σ1RKO mice (2.34 fold). GPx3 is an intracellular enzyme actively released into the plasma so the significance of its elevation in the σ1RKO neural retina is not clear, nor its elevation in the present study of Müller cells.…”

“…Protein was extracted from Müller cells and neural retina isolated from WT and σ1RKO mice per our method [20]. Proteins were subjected to SDS-polyacrylamide gel electrophoresis.…”

NGF Expression in Reelin-Deprived Retinal Cells: A Potential Neuroprotective Effect

“…A downregulation of the proapoptotic factor Bax was detected in parallel (a, b). Real-time PCR data are expressed as fold changes no signs of apoptosis and significant increase in Bcl2 protein in p75 NTR -expressing RGCs would suggest that p75 NTR expression in E-Reeler retinas might drive prosurvival effects, at least in RGCs (Topham and Taylor 2013;Balzamino et al 2014;Ha et al 2014). As previously reported, E-Reeler retina is characterized by a reduced migration and improper positioning of RBCs at the inner nuclear layer .…”

Sigma receptors as potential therapeutic targets for neuroprotection

“…Indeed, overexpression and/or knockdown of sigma-1 receptors has been shown to modulate cellular responses to ER stress in vitro , including phosphorylation levels of PERK or IRE-1, and cleavage of ATF6 elicited by the ER stressor thapsigargin in CHO cells (Hayashi and Su, 2007; Mori et al, 2013). The exact mechanism whereby sigma-1 receptors may be altering the activity or levels of these stress proteins remains under investigation, but may involve direct interaction, as in the case with IRE-1 in CHO cells (Mori et al, 2013), and/or indirectly through transcriptional regulation as seen in retinal cells and human lenses (Ha et al, 2014; Wang et al, 2012). …”