Protein kinase C inhibitors counteract the ethanol effects on myelin basic protein expression in differentiating CG-4 oligodendrocytes
Protein kinase C inhibitors counteract the ethanol effects on myelin basic protein expression in differentiating CG-4 oligodendrocytes
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DOI：
10.1016/s0165-3806(02)00512-6
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发表时间：
2002-11-15
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影响因子：
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通讯作者：
Ellingson, JS
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文献类型：
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作者：
Bichenkov, E;Ellingson, JS
髓磷脂的异常形成似乎是导致与胎儿酒精综合征相关的神经病理学发展的一种缺陷。我们之前使用 CG-4 细胞系表明，25-75 mM EtOH 下调分化少突胶质细胞 (OLG) 中髓磷脂碱性蛋白 (MBP) 的表达，而不影响形态发育 (Dev. Brain Res. 128 (2001) 9)。在这里，我们发现相对较低浓度的 12-佛波醇-13-肉豆蔻酸酯乙酸酯 (PMA) 模拟了 EtOH 引起的 MBP 表达抑制，而不影响形态。 100 mM EtOH 或 1 nM PMA 对 MBP 表达的抑制被蛋白激酶 C (PKC) 的三种抑制剂（双吲哚基马来酰亚胺 1、氯化白屈菜红碱和钙磷蛋白 C）完全抵消，表明 EtOH 通过激活 PKC 下调 MBP 表达。我们研究了 EtOH 激活是否部分归因于 PKC 同工酶表达的上调。在检测的 11 种 PKC 同工酶中，CG-4 OLG 表达了 9 种； PKC α、β1、β2； δ、ε、eta；拉姆达、泽塔；亩;而PKC同工酶γ和θ未检测到。只有五种 PKC 同工酶（α、β1、β2、eta 和 mu）表现出表达的发育变化。然而，在分化的前 2 天（即下调 CG-4 细胞中 MBP 表达的发育阶段），EtOH 不会上调任何 PKC 同工酶的早期表达。 PMA 和 EtOH 的类似作用表明，EtOH 通过激活少突胶质细胞中至少一种佛波酯敏感的 PKC 同工酶来延迟 MBP 表达，而不上调其表达。 (C) 2002 Elsevier Science B.V. 保留所有权利。
Abnormal formation of myelin appears to be one defect contributing to the development of the neuropathology associated with the fetal alcohol syndrome. Using the CG-4 cell line we previously showed that 25-75 mM EtOH downregulates the expression of myelin basic protein (MBP) in differentiating oligodendrocytes (OLGs) without affecting morphological development (Dev. Brain Res. 128 (2001) 9). Here we showed that a relatively low concentration of 12-phorbol-13-myristate acetate (PMA) mimicked the EtOH-caused inhibition of MBP expression without affecting morphology. The inhibition of MBP expression by 100 mM EtOH or 1 nM PMA was completely counteracted by three inhibitors of protein kinase C (PKC), bisindolylmaleimide 1, chelerythrine chloride, and calphostin C, indicating that EtOH downregulated MBP expression by activating PKC. We investigated whether the EtOH activation resulted, in part, from upregulation of the expression of PKC isozymes. Of 11 PKC isozymes examined, CG-4 OLGs expressed nine; PKCs alpha, beta1, beta2; delta, epsilon, eta; lambda, zeta; mu; while PKC isozymes gamma and theta were not detected. Only five PKC isozymes, alpha, beta1, beta2, eta, and mu, displayed developmental changes in expression. However, EtOH did not upregulate the early expression of any PKC isozyme during the first 2 days of differentiation, the developmental stage when it downregulates MBP expression in CG-4 cells. The similar effects of PMA and EtOH indicate that EtOH delays MBP expression by activating at least one phorbol ester-sensitive PKC isozyme in oligodendrocytes without upregulating its expression. (C) 2002 Elsevier Science B.V. All rights reserved.