Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum.
Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum.
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DOI：
10.1523/jneurosci.2518-08.2008
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发表时间：
2008-10-15
期刊：
影响因子：
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通讯作者：
Snyder GL
中科院分区：
文献类型：
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作者：
Nishi A;Kuroiwa M;Miller DB;O'Callaghan JP;Bateup HS;Shuto T;Sotogaku N;Fukuda T;Heintz N;Greengard P;Snyder GL
磷酸二酯酶（PDE）是细胞中cAMP/蛋白激酶a （PKA）信号的关键调节因子。具有不同底物特异性和亚细胞定位的多个pde在神经元中表达。多巴胺在运动和认知功能的调节中起着核心作用。多巴胺的作用主要通过cAMP/PKA信号级联介导，因此受PDE活性控制。通过监测选择性PDE抑制剂调节突触前[如酪氨酸羟化酶（TH）]和突触后[如多巴胺和camp调节的Mr 32 kDa磷酸化蛋白（DARPP-32）] PKA底物磷酸化的能力，我们使用体外和体内生化技术来剖析PDE4和PDE10A在小鼠纹状体多巴胺能神经传递中的作用。PDE4抑制剂罗利普兰诱导多巴胺能末端TH Ser40磷酸化大幅增加，这与体内纹状体多巴胺合成和转换的相应增加有关。罗利普兰通过激活纹状体中腺苷A2A受体信号，诱导纹状体神经元中DARPP-32 Thr34磷酸化优先小幅升高。相比之下，PDE10A抑制剂罂粟碱对TH磷酸化或多巴胺转换没有影响，但却显著增加纹状体神经元中DARPP-32 Thr34和GluR1 Ser845的磷酸化。罂粟碱抑制PDE10A可激活纹状体和纹状顶神经元的cAMP/PKA信号，导致多巴胺D1受体信号增强和多巴胺D2受体信号抑制。这些生化结果得到免疫组织化学数据的支持，显示PDE10A和PDE4在纹状体中的不同定位。这些数据强调了个体大脑富集环核苷酸PDE亚型作为影响多巴胺神经传递的神经精神和神经退行性疾病的治疗靶点的重要性。
Phosphodiesterase (PDE) is a critical regulator of cAMP/protein kinase A (PKA) signaling in cells. Multiple PDEs with different substrate specificities and subcellular localization are expressed in neurons. Dopamine plays a central role in the regulation of motor and cognitive functions. The effect of dopamine is largely mediated through the cAMP/PKA signaling cascade, and therefore controlled by PDE activity. We used in vitro and in vivo biochemical techniques to dissect the roles of PDE4 and PDE10A in dopaminergic neurotransmission in mouse striatum by monitoring the ability of selective PDE inhibitors to regulate phosphorylation of presynaptic [e.g., tyrosine hydroxylase (TH)] and postsynaptic [e.g., dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa (DARPP-32)] PKA substrates. The PDE4 inhibitor, rolipram, induced a large increase in TH Ser40 phosphorylation at dopaminergic terminals that was associated with a commensurate increase in dopamine synthesis and turnover in striatum in vivo. Rolipram induced a small increase in DARPP-32 Thr34 phosphorylation preferentially in striatopallidal neurons by activating adenosine A2A receptor signaling in striatum. In contrast, the PDE10A inhibitor, papaverine, had no effect on TH phosphorylation or dopamine turnover, but instead robustly increased DARPP-32 Thr34 and GluR1 Ser845 phosphorylation in striatal neurons. Inhibition of PDE10A by papaverine activated cAMP/PKA signaling in both striatonigral and striatopallidal neurons, resulting in potentiation of dopamine D1 receptor signaling and inhibition of dopamine D2 receptor signaling. These biochemical results are supported by immunohistochemical data demonstrating differential localization of PDE10A and PDE4 in striatum. These data underscore the importance of individual brain-enriched cyclic-nucleotide PDE isoforms as therapeutic targets for neuropsychiatric and neurodegenerative disorders affecting dopamine neurotransmission.