Blockade of adenosine A_2A receptors downregulates DARPP-32 but increases ERK1/2 activity in striatum of dopamine deficient “weaver” mouse

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• 作者：Konstantinos Botsakis ; Ourania Pavlou ; Paraskevi D. Poulou ; Nikolaos Matsokis ; Fevronia Angelatou
• 关键词：A_2A receptors ; DARPP-32 ; ERK1/2 ; Dopamine deficiency ; “ ; Weaver” ; mutant
• 刊名：Neurochemistry International
• 出版年：2010
• 出版时间：January 2010
• 年：2010
• 卷：56
• 期：2
• 页码：245-249
• 全文大小：329 K

文摘

In the present study we investigated the signal transduction cascade modulated by adenosine A_2A receptors under chronic dopamine deficiency in the “weaver” mouse. We determined the phosphorylation state of cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr34 and of Extracellular Signal-regulated Protein Kinases 1/2 (ERK1/2), under basal conditions and after in vivo stimulation of A_2A receptors by administration of the agonist CGS21680. Our results revealed that the endogenous levels of phospho-DARPPP-32 and phospho-ERK1/2 are elevated in “weaver” striatum probably as an adaptation phenomenon to gradual dopaminergic neurodegeneration appearing in this animal model, characterized as phenocopy of Parkinson's disease. Stimulation of A_2A receptors by CGS21680 further increases phospho-DARPP-32 but downregulates significantly the elevated phospho-ERK1/2 levels bringing them close to those observed in wild type animals. Consistently, blockade of A_2A receptors by MSX-3 (A_2A receptor antagonist) downregulates phospho-DARPP-32 but significantly increases even more the phosphorylation/activation of ERK1/2. These results indicate that under chronic dopamine deficiency (a) the A_2A/cAMP/PKA/DARPP-32 cascade is overactive due to the elevated endogenous phospho-DARPP-32 levels and (b) the A_2A receptor modulatory effect on ERK1/2 signaling is dysregulated exerting opposing action compared to that observed in normal animals (Quiroz et al., 2006), i.e. in “weaver” animals A_2A receptor blockade increases the activity of ERK1/2 cascade. This could be of clinical relevance since A_2A antagonists are already used in clinical trials for ameliorating Parkinson's disease (PD) symptoms.