Linking cocaine to endoplasmic reticulum in striatal neurons: role of glutamate receptors.
Linking cocaine to endoplasmic reticulum in striatal neurons: role of glutamate receptors.
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DOI：
10.1016/j.baga.2011.05.002
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发表时间：
2011-07-01
期刊：
影响因子：
--
通讯作者：
Wang, John Q
中科院分区：
文献类型：
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作者：
Choe, Eun Sang;Ahn, Sung Min;Yang, Ju Hwan;Go, Bok Soon;Wang, John Q
内质网(ER)控制蛋白质折叠。未折叠和错误折叠的蛋白质在内质网中的积累触发内质网应激反应，以加速正常的蛋白质折叠，或者如果不能导致细胞凋亡。内质网应激反应是哺乳动物细胞中一种保守的细胞反应，对各种生理或病理生理刺激敏感。最近的研究揭示，纹状体神经元的这种反应受到精神刺激剂的紧密调制。可卡因和安非他明显著增加了多种内质网应激报告蛋白在背侧纹状体(尾壳核)和其他基底节部位的表达。这种诱发的内质网应激反应是通过激活I组代谢性谷氨酸受体和N-甲基-D-天冬氨酸受体来介导的。这些受体激活产生的汇聚的钙信号激活了c-jun氨基末端激酶通路，从而引发内质网应激反应。对刺激剂暴露的强烈内质网应激反应的发现建立了以前未被认识的刺激剂-内质网偶联。这种可诱导的偶联似乎导致了与各种神经精神和神经退行性疾病相关的兴奋剂的神经毒性。因此，阐明可卡因和其他兴奋剂与内质网联系的细胞机制对于开发治疗兴奋剂毒性引起的神经疾病的治疗药物具有重要意义。
The endoplasmic reticulum (ER) controls protein folding. Accumulation of unfolded and misfolded proteins in the ER triggers an ER stress response to accelerate normal protein folding or if failed to cause apoptosis. The ER stress response is a conserved cellular response in mammalian cells and is sensitive to various physiological or pathophysiological stimuli. Recent studies unravel that this response in striatal neurons is subject to the tight modulation by psychostimulants. Cocaine and amphetamines markedly increased expression of multiple ER stress reporter proteins in the dorsal striatum (caudate putamen) and other basal ganglia sites. This evoked ER stress response is mediated by activation of group I metabotropic glutamate receptors and N-methyl-D-aspartate receptors. Converging Ca2+ signals derived from activation of these receptors activate the c-Jun N-terminal kinase pathway to evoke ER stress responses. The discovery of robust ER stress responses to stimulant exposure establishes a previously unrecognized stimulant-ER coupling. This inducible coupling seems to contribute to neurotoxicity of stimulants related to various neuropsychiatric and neurodegenerative illnesses. Elucidating cellular mechanisms linking cocaine and other stimulants to ER is therefore important for the development of therapeutic agents for treating neurological disorders resulted from stimulant toxicity.