Sigma receptor 1 modulates ER stress and Bcl2 in murine retina.
Sigma receptor 1 (σR1), 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 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 the retina and the mechanisms by which its ligands afford neuroprotection are unclear. We therefore used σR1(-/-) mice to investigate the expression of ER stress genes (BiP/GRP78, Atf6, Atf4, Ire1α) 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 Müller glial cells. BCL2 levels decreased in σR1(-/-) retina concomitantly 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 probably 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 provide new insights into the role of σR1 in retinal neuroprotection.
Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, 1120 15th Street, CB 1101, Augusta, GA 30912-2000, USA.
Yonju
Y
Ha
Arul K
AK
Shanmugam
Shanu
S
Markand
Eric
E
Zorrilla
Vadivel
V
Ganapathy
Sylvia B
SB
Smith
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D063928:Ependymoglial Cells / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017480:Receptors, sigma / Q000172:deficiency / Q000378:metabolism*; D012160:Retina / Q000378:metabolism*; D013997:Time Factors; D059467:Transcriptome / Q000235:genetics; D038203:alpha-Crystallin B Chain / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000097605:Sigma-1 Receptor
D000091342:Endoplasmic Reticulum Chaperone BiP; D048049:Extracellular Signal-Regulated MAP Kinases; D006360:Heat-Shock Proteins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D017480:Receptors, sigma; D038203:alpha-Crystallin B Chain; D051028:bcl-2-Associated X Protein; D000097605:Sigma-1 Receptor; C525420:Cryab protein, mouse; C000717248:Hspa5 protein, mouse