Ha Yonju, Shanmugam Arul K, Markand Shanu, Zorrilla Eric, Ganapathy Vadivel, Smith Sylvia B
Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, 1120 15th Street, CB 1101, Augusta, GA 30912-2000, USA.
Cell Tissue Res. 2014 Apr;356(1):15-27. doi: 10.1007/s00441-013-1774-8. Epub 2014 Jan 28.
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.
西格玛受体1（σR1）是一种位于内质网（ER）和线粒体膜上的非阿片类跨膜蛋白，被认为是一种分子伴侣。当在视网膜细胞死亡的体外和体内模型中使用σR1配体时，已观察到对细胞死亡有显著的保护作用。缺乏σR1的小鼠（σR1（-/-））表现出视网膜神经节细胞的迟发性丧失和视网膜电生理变化（数月后）。σR1在视网膜中的作用及其配体提供神经保护的机制尚不清楚。因此，我们使用σR1（-/-）小鼠来研究内质网应激基因（BiP/GRP78、Atf6、Atf4、Ire1α）的表达以及参与凋亡的蛋白质（BCL2、BAX），并在幼年时检查视网膜转录组。虽然神经视网膜中主要内质网应激基因的表达在一年时间内没有显著变化，但在分离的视网膜穆勒胶质细胞中观察到这些基因有明显变化，尤其是Atf6。在σR1（-/-）视网膜中，BCL2水平随着NFkB和pERK1/2的降低而降低。我们推测，σR1调节视网膜穆勒细胞中的内质网应激，并且σR1在视网膜神经保护中的作用可能涉及BCL2和一些修饰其表达的蛋白质（如ERK、NFκB）。对σR1基因敲除小鼠视网膜转录组的分析数据为σR1在视网膜神经保护中的作用提供了新的见解。
