Sigma 1 receptor: A novel therapeutic target in retinal disease.
Sigma 1 receptor: A novel therapeutic target in retinal disease.
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DOI：
10.1016/j.preteyeres.2018.07.003
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发表时间：
2018-11
影响因子：
17.8
通讯作者：
Bollinger KE
中科院分区：
文献类型：
--
作者：
Smith SB;Wang J;Cui X;Mysona BA;Zhao J;Bollinger KE
视网膜退行性疾病是全世界无法治愈的失明的主要原因，迫切需要对这些疾病进行有效的治疗。跨膜蛋白Sigma 1受体（Sig1R）是治疗视网膜疾病的新靶点。这种神秘的蛋白质是一种进化分离物，与任何其他蛋白质都没有已知的同源性。Sig1R最初被认为是一种阿片受体。这种观念已被消除，最近的药理学和分子研究表明，它是一种多能调节剂，具有许多生物学功能，其中许多与视网膜疾病有关。本文综述了Sig1R的发现和早期的药理学研究，这些研究导致了Sig1R基因的克隆和其晶体结构的最终阐明。直到20世纪90年代末，Sig1R在眼睛中的研究才被报道，但从那时起，人们对Sig1R作为视网膜疾病靶点的潜在作用越来越感兴趣。目前的研究主要集中在阐明Sig1R在视网膜中的作用机制，包括钙调节、氧化应激调节、离子通道调节和分子伴侣活性。机制研究已在分离的视网膜细胞中进行，如m<s:1>神经胶质细胞、小胶质细胞、视神经头星形胶质细胞和视网膜神经节细胞以及完整的视网膜。几项令人信服的研究提供了强有力的体内神经保护作用，以防止神经节细胞损失和光感受器细胞损失。还描述了在Sig1R缺失的各种视网膜疾病模型中检查视网膜结构/功能的研究，并揭示与表达Sig1R的动物的视网膜相比，这些表型加速。过去20年的研究分析表明，Sig1R在调节视网膜细胞应激中起着关键作用，并有望成为视网膜神经退行性疾病的靶点。
Retinal degenerative diseases are major causes of untreatable blindness worldwide and efficacious treatments for these diseases are sorely needed. A novel target for treatment of retinal disease is the transmembrane protein Sigma 1 Receptor (Sig1R). This enigmatic protein is an evolutionary isolate with no known homology to any other protein. Sig1R was originally thought to be an opioid receptor. That notion has been dispelled and more recent pharmacological and molecular studies suggest that it is a pluripotent modulator with a number of biological functions, many of which are relevant to retinal disease. This review provides an overview of the discovery of Sig1R and early pharmacologic studies that led to the cloning of the Sig1R gene and eventual elucidation of its crystal structure. Studies of Sig1R in the eye were not reported until the late 1990s, but since that time there has been increasing interest in the potential role of Sig1R as a target for retinal disease. Studies have focused on elucidating the mechanism(s) of Sig1R function in retina including calcium regulation, modulation of oxidative stress, ion channel regulation and molecular chaperone activity. Mechanistic studies have been performed in isolated retinal cells, such as Müller glial cells, microglial cells, optic nerve head astrocytes and retinal ganglion cells as well as in the intact retina. Several compelling studies have provided evidence of powerful in vivo neuroprotective effects against ganglion cell loss as well as photoreceptor cell loss. Also described are studies that have examined retinal structure/function in various models of retinal disease in which Sig1R is absent and reveal that these phenotypes are accelerated compared to retinas of animals that express Sig1R. The collective evidence from analysis of studies over the past 20 years is that Sig1R plays a key role in modulating retinal cellular stress and that it holds great promise as a target in retinal neurodegenerative disease.
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DOI：
10.1126/science.1166127
发表时间：
2009-02-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fontanilla D;Johannessen M;Hajipour AR;Cozzi NV;Jackson MB;Ruoho AE
通讯作者：
Ruoho AE
影响因子：
4.4
作者：
Dun, Ying;Thangaraju, Muthusamy;Smith, Sylvia B.
通讯作者：
Smith, Sylvia B.
影响因子：
15.9
作者：
Barber, AJ;Lieth, E;Gardner, TW
通讯作者：
Gardner, TW
影响因子：
3.6
作者：
Dun, Y;Mysona, B;Smith, SB
通讯作者：
Smith, SB
影响因子：
5
作者：
Bucolo, C;Marrazzo, A;Drago, F
通讯作者：
Drago, F