Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation
Sigma-1 receptors at galactosylceramide-enriched lipid microdomains regulate oligodendrocyte differentiation
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DOI：
10.1073/pnas.0402890101
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发表时间：
2004-10-12
影响因子：
11.1
通讯作者：
Su, TP
中科院分区：
文献类型：
--
作者：
Hayashi, T;Su, TP
在大脑中，髓磷脂通过在轴突处提供绝缘而在调节神经传导和神经递质释放方面是重要的。髓磷脂是分化的少突胶质细胞（OL）的特化但连续的片状结构，其富含脂质，特别是源自内质网（ER）的半乳糖神经酰胺（GalCer）。已知GalCer影响OL分化。然而，GalCer影响OL分化的机制还不清楚。我们证明Sigma-1受体（Sig-1 Rs）存在于NG 108细胞ER富脂位点的洗涤剂不溶性脂质微区中，它在ER合成脂质的区室化/转运和细胞分化中非常重要。在这项研究中，我们使用大鼠原代海马培养物，发现Sig-1 Rs在成熟OLs的整个髓鞘层中的ER脂滴样结构处形成GalCer富集的脂筏。在大鼠OL祖细胞（CG-4细胞）中，随着细胞分化，脂筏驻留的Sig-1 Rs和GalCer水平增加。Sig-1 Rs还增加发育中大鼠大脑的OL和髓鞘。Sig-1 R、GalCer和胆固醇共定位，并且对Triton X-100增溶具有抗性。用Sig-1 R激动剂处理细胞或通过在CG-4细胞中过表达Sig-1 R在脂筏处靶向Sig-1 R增强分化，而通过转染功能显性阴性Sig-1 R减少脂筏处的Sig-1 R减弱分化。此外，Sig-1 R siRNA抑制分化。我们的研究结果表明，在大脑中，Sig-1 Rs靶向含GalCer的脂质微结构域对于OL分化是重要的，并且Sig-1 Rs可能在某些脱髓鞘疾病的发病机制中起重要作用。
In the brain, myelin is important in regulating nerve conduction and neurotransmitter release by providing insulation at axons. Myelin is a specialized yet continuous sheet structure of differentiated oligodendrocytes (OLs) that is enriched in lipids, specifically galactosylceramides (GalCer) originated at the endoplasmic reticulum (ER). GalCer are known to affect OL differentiation. However, the mechanism whereby GalCer affect OL differentiation is not well understood. Sigma-1 receptors (Sig-1Rs), shown by us to exist in detergent-insoluble lipid microdomains at lipid-enriched loci of ER in NG108 cells, are important in the compartmentalization/ transport of ER-synthesized lipids and in cellular differentiation. In this study, we used rat primary hippocampal cultures and found that Sig-1Rs form GalCer-enriched lipid rafts at ER lipid droplet-like structures in the entire myelin sheet of mature OLs. In rat OL progenitors (CG-4 cells), levels of lipid raft-residing Sig-1Rs and GalCer increase as cells differentiate. Sig-1Rs also increase in OLs and myelin of developing rat brains. Sig-1R, GalCer, and cholesterol are colocalized and are resistant to the Triton X-100 solubilization. Treating cells with a Sig-1R agonist or targeting Sig-1Rs at lipid rafts by overexpression of Sig-1Rs in CG-4 cells enhances differentiation, whereas reducing Sig-1Rs at lipid rafts by transfection of functionally dominant-negative Sig-1Rs attenuates differentiation. Furthermore, Sig-1R siRNA inhibits differentiation. Our findings indicate that, in the brain, Sig-1Rs targeting GalCer-containing lipid microdomains are important for OL differentiation and that Sig-1Rs may play an important role in the pathogenesis of certain demyelinating diseases.