THERAPEUTIC TARGETING OF 'DARPP-32': A KEY SIGNALING MOLECULE IN THE DOPIMINERGIC PATHWAY FOR THE TREATMENT OF OPIATE ADDICTION
| Autor: | Mahajan, Supriya D., Aalinkeel, Ravikumar, Reynolds, Jessica L., Nair, Bindukumar B., Sykes, Donald E., Hu, Zihua, Bonoiu, Adela, Ding, Hong, Prasad, Paras N., Schwartz, Stanley A. |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Narcotics
Dopamine and cAMP-Regulated Phosphoprotein 32 Reverse Transcriptase Polymerase Chain Reaction Receptors Dopamine D1 Gene Expression Opioid-Related Disorders Transfection Article Heroin Image Processing Computer-Assisted Humans RNA Small Interfering Extracellular Signal-Regulated MAP Kinases Cells Cultured Oligonucleotide Array Sequence Analysis |
| Popis: | 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 mu-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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|