Activation of AP-1 and CRE-dependent gene expression via μ-opioid receptor
Activation of AP-1 and CRE-dependent gene expression via μ-opioid receptor
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DOI：
10.1111/j.1471-4159.2004.02524.x
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发表时间：
2004-08-01
影响因子：
4.7
通讯作者：
Przewlocki, R
中科院分区：
文献类型：
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作者：
Bilecki, W;Wawrzczak-Bargiela, A;Przewlocki, R
阿片类药物成瘾依赖于药物诱导的神经可塑性变化，并以基因表达的改变为基础。转录因子Ca ~（2+）/cAMP反应元件结合蛋白（CREB）和激活蛋白1（AP-1）可能是阿片调节信号转导途径和基因表达调控的直接联系。用阿片类刺激CREB活性的Neuro 2a莫尔神经母细胞瘤细胞的急性治疗;延长治疗使其正常化，而从药物中撤出再次引起磷酸化CREB水平的增加。蛋白激酶C负责急性阿片类药物给药后的转录激活，而cAMP途径在戒断过程中激活类似的机制，使CREB成为一种对阿片类药物信号的存在或戒断做出反应的“触发器”。除了CREB磷酸化水平升高，CRE结合活性和CRE元件调控的荧光素酶报告基因的表达在单次给药后和从长期阿片类药物治疗中撤出期间增加。沿着CREB，AP-1结合活性和AP-1定向转录在单次给药后和戒断期间被刺激。这些结果提供了证据表明，无论是单一阿片类药物管理和阿片类药物戒断激活CREB和CRE依赖的转录机制，通过不同的细胞内信号通路。
Addiction to opiates depend on drug-induced neuroplastic changes and are underlain by alterations of gene expression. Transcription factors Ca2+/cAMP responsive element binding protein (CREB) and activator protein 1 (AP-1) may constitute a direct link between the opioid-regulated signal transduction pathways and modulation of gene expression. Acute treatment of Neuro2a MOR neuroblastoma cells with opioids stimulated CREB activity; prolonged treatment normalized it, while withdrawal from the drug again elicited an increase in phosphorylated CREB levels. Protein kinase C was responsible for the activation of transcription following acute opioid administration whereas the cAMP pathway activated similar mechanisms during withdrawal, making CREB a kind of 'a trigger' reacting to the presence or withdrawal of the opioid signal. Apart from the elevated CREB phosphorylation, CRE binding activity and expression of luciferase reporter gene regulated by CRE elements were increased after single administration and during withdrawal from the prolonged opioid treatment. Along with CREB, AP-1 binding activity and AP-1-directed transcription were stimulated after single administration and during withdrawal from the opioid. These results provide evidence that both single opioid administration and opioid withdrawal activate CREB and CRE-dependent transcriptional mechanisms via distinct intracellular signaling pathways.