Therapeutic targeting of "DARPP-32": a key signaling molecule in the dopiminergic pathway for the treatment of opiate addiction.
Therapeutic targeting of "DARPP-32": a key signaling molecule in the dopiminergic pathway for the treatment of opiate addiction.
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DOI：
10.1016/s0074-7742(09)88008-2
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发表时间：
2009
影响因子：
--
通讯作者：
Schwartz, Stanley A.
中科院分区：
文献类型：
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作者：
Mahajan, Supriya D.;Aalinkeel, Ravikumar;Reynolds, Jessica L.;Nair, Bindukumar B.;Sykes, Donald E.;Hu, Zihua;Bonaiu, Adela;Ding, Hong;Prasad, Paras N.;Schwartz, Stanley A.
32 kDa多巴胺和腺苷3′，5 ′-一磷酸调节磷蛋白（DARPP-32）被认为是药物成瘾发病机制的关键。阿片类药物通过μ-受体作用于脑中的多巴胺能系统并调节DARPP-32磷蛋白的表达，DARPP-32磷蛋白是细胞外信号调节激酶（ERK）信号级联活性的重要介导物，ERK信号级联的激活代表了药物诱导的神经长时程突触可塑性变化的激动人心的联系。使用针对DARPP-32的siRNA沉默DARPP-32可能提供克服药物成瘾的新的基因治疗策略。在这项研究中，我们研究了阿片类药物（海洛因）对D1受体（D1 R）和DARPP-32表达的影响，并评估了DARPP-32-siRNA基因沉默对体外原代正常人星形胶质细胞（NHA）中蛋白磷酸酶-1（PP-1）、ERK和cAMP反应元件结合（CREB）基因表达的影响。我们的研究结果表明，海洛因显着上调D1 R和DARPP-32基因的表达，DARPP-32在NHA细胞中的沉默导致的下游效应分子，如PP-1，ERK和CREB的活性的显着调制，这是已知的阿片类药物滥用诱导的长期神经可塑性的变化中发挥重要作用。这些发现有可能促进基于DARPP 32 siRNA的药物治疗药物的开发。
The 32-kDa dopamine- and adenosine 3′,5′-monophosphate-regulated phosphoprotein (DARPP-32) is recognized to be critical to the pathogenesis of drug addiction. Opiates via the μ-receptor act on the dopaminergic system in the brain and modulates the expression of DARPP-32 phosphoprotein which is an important mediator of the activity of the extracellular signal-regulated kinase (ERK) signaling cascades, the activation of which represents an exciting nexus for drug-induced changes in neural long-term synaptic plasticity. Silencing of DARPP-32 using an siRNA against DARPP-32 may provide a novel gene therapy strategy to overcome drug addiction. In this study, we investigated the effect of the opiate (heroin) on D1 receptor (D1R) and DARPP-32 expression and additionally, evaluated the effects of DARPP-32-siRNA gene silencing on protein phosphatase-1 (PP-1), ERK, and cAMP response element-binding (CREB) gene expression in primary normal human astrocytes (NHA) cells in vitro. Our results indicate that heroin significantly upregulated both D1R and DARPP-32 gene expression, and that DARPP-32 silencing in the NHA cells resulted in the significant modulation of the activity of downstream effector molecules such as PP-1, ERK, and CREB which are known to play an important role in opiate abuse-induced changes in long-term neural plasticity. These findings have the potential to facilitate the development of DARPP32 siRNA-based therapeutics against drug addiction.