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首页> 外文期刊>The European Journal of Neuroscience >Regulation of DARPP-32 Thr75 phosphorylation by neurotensin in neostriatal neurons: involvement of glutamate signalling.
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Regulation of DARPP-32 Thr75 phosphorylation by neurotensin in neostriatal neurons: involvement of glutamate signalling.

机译：新纹状体神经元中神经降压素对DARPP-32 Thr75磷酸化的调节：谷氨酸信号的参与。

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摘要

Neurotensin is a neuropeptide involved in dopaminergic signalling. We have recently reported that neurotensin stimulates the phosphorylation of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa) at Thr34 (PKA-site) by activating dopamine D1-type receptors in neostriatal neurons. DARPP-32 is also phosphorylated by cyclin-dependent kinase 5 on Thr75, and the phosphorylated form of DARPP-32 at Thr75 inhibits protein kinase (PKA) activity. In this study, we examined the effect of neurotensin on DARPP-32 Thr75 phosphorylation using mouse neostriatal slices. Neurotensin decreased the level of phospho-Thr75 DARPP-32 at 2 min of incubation, maximally to about 50% of control at a concentration of 1 micro m. Pretreatment with a combined neurotensin receptor type 1 (NTR1)/type 2 (NTR2) antagonist, SR142948, reduced the basal level of phospho-Thr75 DARPP-32 and abolished the ability of neurotensin to decrease DARPP-32 Thr75 phosphorylation. However, neither an NTR1 antagonist, SR48692, an NTR2 antagonist, levocabastine, nor the two combined affected the basal level and the neurotensin-mediated decrease in DARPP-32 Thr75 phosphorylation. The effect of neurotensin was abolished by tetrodotoxin (TTX) or MK801 plus CNQX, but not by SCH23390 or raclopride. These results indicate that neurotensin stimulates the release of glutamate by activating a hypothesized unidentified neurotensin receptor, resulting in the dephosphorylation of DARPP-32 at Thr75 by activating NMDA and AMPA receptors expressed at medium spiny neurons. Thus, neurotensin, by removing the inhibition of PKA by phospho-Thr75 DARPP-32, potentiates its signalling via the dopamine/D1 receptor/PKA/phospho-Thr34 DARPP-32/PP-1 cascade.
机译：神经降压素是一种参与多巴胺能信号传导的神经肽。我们最近报道，神经降压素通过激活新纹状体神经元中的多巴胺D1型受体刺激Thr34（多巴胺位点）处的DARPP-32（多巴胺和cAMP调节的Mr 32 kDa磷酸化蛋白）的磷酸化。 DARPP-32也被Thr75上的细胞周期蛋白依赖性激酶5磷酸化，而DARPP-32在Thr75上的磷酸化形式抑制了蛋白激酶（PKA）活性。在这项研究中，我们使用小鼠新纹状体切片检查了神经降压素对DARPP-32 Thr75磷酸化的影响。在培养2分钟后，神经降压素降低了磷酸化Thr75 DARPP-32的水平，在浓度为1微米时最大降低至对照的50％。联合使用神经紧张素受体1型（NTR1）/ 2型（NTR2）拮抗剂SR142948进行的预处理降低了磷酸Thr75 DARPP-32的基础水平，并废除了神经降压素降低DARPP-32 Thr75磷酸化的能力。但是，无论是NTR1拮抗剂SR48692，NTR2拮抗剂左卡泊汀，还是两者都不能影响基础水平和神经降压素介导的DARPP-32 Thr75磷酸化水平的降低。河豚毒素（TTX）或MK801加CNQX消除了神经降压素的作用，但SCH23390或雷洛必利则没有。这些结果表明，神经降压素通过激活假定的未鉴定的神经降压素受体来刺激谷氨酸的释放，从而通过激活在中等多刺的神经元表达的NMDA和AMPA受体导致DARPP-32在Thr75处去磷酸化。因此，神经降压素通过消除磷酸化-Thr75 DARPP-32对PKA的抑制作用，通过多巴胺/ D1受体/ PKA /磷酸化-Thr34 DARPP-32 / PP-1级联作用增强其信号传导。

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