Sigma receptor 1 modulates ER stress and Bcl2 in murine retina

Sigma receptor 1 (sigma R1), a non-opiate transmembrane protein located on endoplasmic reticulum (ER) and mitochondrial membranes, is considered to be a molecular chaperone. Marked protection against cell death has been observed when ligands for sigma R1 have been used in in vitro and in vivo models of retinal cell death. Mice lacking sigma R1 (sigma R1 (-/-)) manifest late-onset loss of retinal ganglion cells and retinal electrophysiological changes (after many months). The role of sigma R1 in the retina and the mechanisms by which its ligands afford neuroprotection are unclear. We therefore used sigma R1 (-/-) mice to investigate the expression of ER stress genes (BiP/GRP78, Atf6, Atf4, Ire1 alpha) and proteins involved in apoptosis (BCL2, BAX) and to examine the retinal transcriptome at young ages. Whereas no significant changes occurred in the expression of major ER stress genes (over a period of a year) in neural retina, marked changes were observed in these genes, especially Atf6, in isolated retinal Muller glial cells. BCL2 levels decreased in sigma R1 (-/-) retina concomitantly with decreases in NFkB and pERK1/2. We postulate that sigma R1 regulates ER stress in retinal Muller cells and that the role of sigma R1 in retinal neuroprotection probably involves BCL2 and some of the proteins that modify its expression (such as ERK, NF kappa B). Data from the analysis of the retinal transcriptome of sigma R1 null mice provide new insights into the role of sigma R1 in retinal neuroprotection.