Department of Physiology and Pharmacology, Institute of Biomedical Sciences, Chang-Gung University, 259 Wen-Hwa 1st Road, Tao-Yuan, Taiwan, ROC.
ASN Neuro. 2012 Sep 24;4(6):371-82. doi: 10.1042/AN20120013.
The short and long isoforms of the dopamine D2 receptor (D2S and D2L respectively) are highly expressed in the striatum. Functional D2 receptors activate an intracellular signalling pathway that includes a cAMP-independent route involving Akt/GSK3 (glycogen synthase kinase 3). To investigate the Akt/GSK3 response to the seldom-studied D2S receptor, we established a rat D2S receptor-expressing cell line [HEK (human embryonic kidney)-293/rD2S]. We found that in HEK-293/rD2S cells, the D2/D3 agonists bromocriptine and quinpirole significantly induced Akt and GSK3 phosphorylation, as well as ERK1/2 (extracellular-signal-regulated kinase 1/2) activation. The D2S receptor-induced Akt signals were profoundly inhibited by the internalization blockers monodansyl cadaverine and concanavalin A. Activation of the D2S receptor in HEK-293/rD2S cells appeared to trigger Akt/phospho-Akt translocation to the cell membrane. In addition to our cell culture experiments, we studied D2 receptor-dependent Akt in vivo by systemic administration of the D2/D3 agonist quinpirole. The results show that quinpirole evoked Akt-Ser473 phosphorylation in the ventral striatum. Furthermore, intra-accumbens administration of wortmannin, a PI3K (phosphoinositide 3-kinase) inhibitor, significantly suppressed the quinpirole-evoked behavioural activation. Overall, we demonstrate that activation of the dopamine D2S receptor stimulates Akt/GSK3 signalling. In addition, in vivo Akt activity in the ventral striatum appears to play an important role in systemic D2/D3 agonist-induced behavioural activation.
多巴胺 D2 受体（分别为 D2S 和 D2L）的短和长亚型在纹状体中高度表达。功能性 D2 受体激活包括 Akt/GSK3（糖原合酶激酶 3）在内的细胞内信号通路，该通路不依赖 cAMP。为了研究很少研究的 D2S 受体的 Akt/GSK3 反应，我们建立了大鼠 D2S 受体表达细胞系[HEK（人胚肾）-293/rD2S]。我们发现，在 HEK-293/rD2S 细胞中，D2/D3 激动剂溴麦角隐亭和喹吡罗显著诱导 Akt 和 GSK3 磷酸化，以及 ERK1/2（细胞外信号调节激酶 1/2）的激活。D2S 受体诱导的 Akt 信号被内化阻滞剂单丹磺酰尸胺和伴刀豆球蛋白 A 强烈抑制。D2S 受体在 HEK-293/rD2S 细胞中的激活似乎触发 Akt/磷酸化-Akt 向细胞膜易位。除了我们的细胞培养实验外，我们还通过系统给予 D2/D3 激动剂喹吡罗来研究体内 D2 受体依赖性 Akt。结果表明，喹吡罗在腹侧纹状体中诱导 Akt-Ser473 磷酸化。此外，Accumbens 内给予 PI3K（磷酸肌醇 3-激酶）抑制剂 wortmannin 可显著抑制喹吡罗引起的行为激活。总的来说，我们证明 D2S 受体的激活刺激 Akt/GSK3 信号。此外，腹侧纹状体中的体内 Akt 活性似乎在系统给予 D2/D3 激动剂引起的行为激活中起重要作用。
