Role of adrenoceptors in the regulation of dopamine/DARPP-32 signaling in neostriatal neurons.
Role of adrenoceptors in the regulation of dopamine/DARPP-32 signaling in neostriatal neurons.
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DOI：
10.1111/j.1471-4159.2010.06668.x
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发表时间：
2010-05
影响因子：
4.7
通讯作者：
Nishi A
中科院分区：
文献类型：
--
作者：
Hara M;Fukui R;Hieda E;Kuroiwa M;Bateup HS;Kano T;Greengard P;Nishi A
对帕金森病动物模型的研究表明，去甲肾上腺素神经元的变性与运动缺陷有关。几种类型的肾上腺素受体在新纹状体神经元中高度表达。然而，这些受体对纹状体信号通路的选择性作用尚未得到表征。在这项研究中，我们研究了多巴胺/DARPP-32信号调节中的作用，通过分析DARPP-32磷酸化在Thr 34（PKA位点）在小鼠新纹状体切片。β1-肾上腺素能受体的激活诱导DARPP-32磷酸化的快速和短暂的增加。α2-肾上腺素受体的激活也诱导DARPP-32磷酸化的快速和短暂增加，随后降低至低于基础水平。此外，α2-肾上腺素受体的激活减弱，α2-肾上腺素受体的阻断增强多巴胺D1和腺苷A2 A受体/DARPP-32信号传导。去甲肾上腺素能神经元的化学损伤模拟α2-肾上腺素受体阻断剂的作用。在α2-肾上腺素受体阻断的条件下，多巴胺D2受体诱导的DARPP-32磷酸化的降低被减弱。我们的数据表明，β1-和α2-肾上腺素受体调节DARPP-32磷酸化的新纹状体神经元。α2-肾上腺素受体激活Gi可拮抗D1和A2 A受体介导的Gs/PKA信号通路，从而增强D2受体/Gi信号通路。因此，α2-肾上腺素受体可能是治疗帕金森病的一个治疗靶点。
Studies in animal models of Parkinson's disease have revealed that degeneration of noradrenaline neurons is involved in the motor deficits. Several types of adrenoceptors are highly expressed in neostriatal neurons. However, the selective actions of these receptors on striatal signaling pathways have not been characterized. In this study, we investigated the role of adrenoceptors in the regulation of dopamine/DARPP-32 signaling by analyzing DARPP-32 phosphorylation at Thr34 (PKA-site) in mouse neostriatal slices. Activation of β1-adrenoceptors induced a rapid and transient increase in DARPP-32 phosphorylation. Activation of α2-adrenoceptors also induced a rapid and transient increase in DARPP-32 phosphorylation, which subsequently decreased below basal levels. In addition, activation of α2-adrenoceptors attenuated, and blockade of α2-adrenoceptors enhanced dopamine D1 and adenosine A2A receptor/DARPP-32 signaling. Chemical lesioning of noradrenergic neurons mimicked the effects of α2-adrenoceptor blockade. Under conditions of α2-adrenoceptor blockade, the dopamine D2 receptor-induced decrease in DARPP-32 phosphorylation was attenuated. Our data demonstrate that β1- and α2-adrenoceptors regulate DARPP-32 phosphorylation in neostriatal neurons. Gi activation by α2-adrenoceptors antagonizes Gs/PKA signaling mediated by D1 and A2A receptors in striatonigral and striatopallidal neurons, respectively, and thereby enhances D2 receptor/Gi signaling in striatopallidal neurons. α2-adrenoceptors may therefore be a therapeutic target for the treatment of Parkinson's disease.
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影响因子：
3.6
作者：
Grondin, R;Tahar, AH;Bédard, PJ
通讯作者：
Bédard, PJ
影响因子：
25
作者：
Bateup, Helen S.;Svenningsson, Per;Kuroiwa, Mahomi;Gong, Shiaoching;Nishi, Akinori;Heintz, Nathaniel;Greengard, Paul
通讯作者：
Greengard, Paul
影响因子：
4.7
作者：
Kuroiwa, Mahomi;Bateup, Helen S.;Nishi, Akinori
通讯作者：
Nishi, Akinori
影响因子：
3.4
作者：
DICKINSON, SL;GADIE, B;TULLOCH, IF
通讯作者：
TULLOCH, IF
影响因子：
3.3
作者：
Holmberg, M;Scheinin, M;Miettinen, R
通讯作者：
Miettinen, R