Svenningsson P, Lindskog M, Rognoni F, Fredholm B B, Greengard P, Fisone G
Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
Neuroscience. 1998 May;84(1):223-8. doi: 10.1016/s0306-4522(97)00510-1.
In the striatum, adenosine A2A and dopamine D1 receptors are segregated in striatopallidal and striatonigral projection neurons, respectively. In this study, we have examined the effects of activating adenosine A2A and dopamine D1 receptors on the state of phosphorylation of DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein of mol. wt 32,000), a potent endogenous regulator of protein phosphatase-1 that is highly expressed in striatal medium-sized spiny neurons. In rat striatal slices, the D1 receptor agonist SKF 81297 and the A2A receptor agonist CGS 21680 transiently increased the levels of phosphorylated DARPP-32 in a concentration-dependent manner. In the same preparation, the two agonists were also able to induce a significant increase in cyclic AMP formation. When striatal slices were incubated with a combination of CGS 21680 and SKF 81297, the effects of the two agonists on both DARPP-32 phosphorylation and cyclic AMP formation were additive. The maximal effects of SKF 81297 and CGS 21680 on DARPP-32 phosphorylation were of similar magnitude, and were completely abolished by the cyclic AMP-dependent protein kinase inhibitor, Rp-cAMPS. The present results show that DARPP-32 phosphorylation in the striatum is stimulated by adenosine, acting on A2A receptors, and dopamine, acting on D1 receptors, and that cyclic AMP is the mediator in both cases. Our data also suggest that dopamine and adenosine regulate the state of phosphorylation of DARPP-32 in distinct sub-populations of medium-sized spiny neurons expressing dopamine D1 and adenosine A2A receptors, respectively.
在纹状体中，腺苷A2A受体和多巴胺D1受体分别在纹状体苍白球和纹状体黑质投射神经元中分隔分布。在本研究中，我们检测了激活腺苷A2A受体和多巴胺D1受体对DARPP-32（分子量为32,000的多巴胺和环磷酸腺苷调节的磷蛋白）磷酸化状态的影响，DARPP-32是一种强效的内源性蛋白磷酸酶-1调节剂，在纹状体中等大小棘状神经元中高度表达。在大鼠纹状体切片中，D1受体激动剂SKF 81297和A2A受体激动剂CGS 21680以浓度依赖性方式短暂增加了磷酸化DARPP-32的水平。在同一制剂中，这两种激动剂也能够诱导环磷酸腺苷生成显著增加。当纹状体切片与CGS 21680和SKF 81297联合孵育时，两种激动剂对DARPP-32磷酸化和环磷酸腺苷生成的作用是相加的。SKF 81297和CGS 21680对DARPP-32磷酸化的最大作用幅度相似，并被环磷酸腺苷依赖性蛋白激酶抑制剂Rp-cAMPS完全消除。目前的结果表明，纹状体中DARPP-32的磷酸化受到作用于A2A受体的腺苷和作用于D1受体的多巴胺的刺激，并且在这两种情况下环磷酸腺苷都是介质。我们的数据还表明，多巴胺和腺苷分别在表达多巴胺D1和腺苷A2A受体的中等大小棘状神经元的不同亚群中调节DARPP-32的磷酸化状态。
