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Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine

机译：DARPP-32磷酸化参与咖啡因的刺激作用

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摘要

Caffeine has been imbibed since ancient times in tea and coffee, and more recently in colas. Caffeine owes its psychostimulant action to a blockade of adenosine A_2A receptors, but little is known about its intracellular mechanism of action. Here we show that the stimulatory effect of caffeine on motor activity in mice was greatly reduced following genetic deletion of DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein of relative molecular mass 32,000). Results virtually identical to those seen with caffeine were obtained with the selective A_2A antagonist SCH 58261. The depressant effect of the A_2A receptor agonist, CGS 21680, on motor activity was also greatly attenuated in DARPP-32 knockout mice. In support of a role for DARPP-32 in the action of caffeine, we found that, in striata of intact mice, caffeine increased the state of phosphorylation of DARPP-32 at Thr 75. Caffeine increased Thr 75 phosphorylation through inhibition of PP-2A-catalysed dephosphorylation, rather than through stimulation of cyclin-dependent kinase 5 (Cdk5)-cata-lysed phosphorylation, of this residue. Together, these studies demonstrate the involvement of DARPP-32 and its phosphory-lation/dephosphorylation in the stimulant action of caffeine.
机译：咖啡因从远古时代就开始在茶和咖啡中吸收，最近在可乐中也被吸收。咖啡因的精神兴奋作用归因于腺苷A_2A受体的阻滞，但对其细胞内作用机制了解甚少。在这里，我们显示了咖啡因对小鼠运动活动的刺激作用在DARPP-32（相对分子质量为32,000的多巴胺和环AMP调节的磷蛋白）的基因缺失后大大降低了。选择性A_2A拮抗剂SCH 58261获得了与咖啡因几乎相同的结果。在DARPP-32基因敲除小鼠中，A_2A受体激动剂CGS 21680对运动活性的抑制作用也大大减弱。为了支持DARPP-32在咖啡因中的作用，我们发现，在完整小鼠的纹状体中，咖啡因增加了Thr 75时DARPP-32的磷酸化状态。咖啡因通过抑制PP-2A增加了Thr 75磷酸化。 -残基的催化磷酸化，而不是通过细胞周期蛋白依赖性激酶5（Cdk5）催化的磷酸化刺激。总之，这些研究表明DARPP-32及其磷酸化/去磷酸化与咖啡因的刺激作用有关。

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