Medium spiny neurons (MSNs) expressing dopamine D1 receptor (D1R) or D2 receptor (D2R) are major components of the striatum. Stimulation of D1R activates protein kinase A (PKA) through Golf to increase neuronal activity, while D2R stimulation inhibits PKA through Gi. Adenosine A2A receptor (A2AR) coupled to Golf is highly expressed in D2R-MSNs within the striatum. However, how dopamine and adenosine co-operatively regulate PKA activity remains largely unknown. Here, we measured Rap1gap serine 563 phosphorylation to monitor PKA activity and examined dopamine and adenosine signals in MSNs. We found that a D1R agonist increased Rap1gap phosphorylation in striatal slices and in D1R-MSNs in vivo. A2AR agonist CGS21680 increased Rap1gap phosphorylation, and pretreatment with the D2R agonist quinpirole blocked this effect in striatal slices. D2R antagonist eticlopride increased Rap1gap phosphorylation in D2R-MSNs in vivo, and the effect of eticlopride was blocked by the pretreatment with the A2AR antagonist SCH58261. These results suggest that adenosine positively regulates PKA in D2R-MSNs through A2AR, while this effect is blocked by basal dopamine in vivo. Incorporating computational model analysis, we propose that the shift from D1R-MSNs to D2R-MSNs or vice versa appears to depend predominantly on a change in dopamine concentration.

中文翻译：

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多巴胺和腺苷信号之间的平衡调节纹状体中棘神经元中的PKA / Rap1途径。

表达多巴胺D1受体（D1R）或D2受体（D2R）的中棘神经元（MSN）是纹状体的主要成分。D1R刺激通过Golf激活蛋白激酶A（PKA）以增加神经元活性，而D2R刺激通过Gi抑制PKA。与Golf偶联的腺苷A2A受体（A2AR）在纹状体内的D2R-MSN中高度表达。然而，多巴胺和腺苷如何协同调节PKA活性仍然未知。在这里，我们测量Rap1gap丝氨酸563磷酸化以监测PKA活性，并检查MSN中的多巴胺和腺苷信号。我们发现D1R激动剂在体内增加纹状体切片和D1R-MSNs中Rap1gap的磷酸化。A2AR激动剂CGS21680增加了Rap1gap的磷酸化作用，而D2R激动剂喹吡罗的预处理可阻止纹状体切片中的这种作用。D2R拮抗剂艾替洛必利增加了D2R-MSNs体内Rap1gap的磷酸化，而艾替必利的作用被A2AR拮抗剂SCH58261预处理所阻断。这些结果表明，腺苷可通过A2AR积极调节D2R-MSNs中的PKA，而这种作用在体内被基础多巴胺所阻断。结合计算模型分析，我们建议从D1R-MSNs到D2R-MSNs的转变，反之亦然，似乎主要取决于多巴胺浓度的变化。