Phosphodiesterase 10A (PDE10A): Regulator of Dopamine Agonist-Induced Gene Expression in the Striatum.
Phosphodiesterase 10A (PDE10A): Regulator of Dopamine Agonist-Induced Gene Expression in the Striatum.
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DOI：
10.3390/cells11142214
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发表时间：
2022-07-16
期刊：
影响因子：
6
通讯作者：
Steiner, Heinz
中科院分区：
文献类型：
--
作者：
Bonate, Ryan;Kurek, Gabriela;Hrabak, Michael;Patterson, Santanna;Padovan-Neto, Fernando;West, Anthony R.;Steiner, Heinz
多巴胺和其他神经递质有可能通过基因调控诱导纹状体的神经可塑性。多巴胺受体介导的基因调控依赖于第二信使级联反应，包括环核苷酸将信号从突触传递到细胞核。磷酸二酯酶（PDEs）催化环核苷酸，从而有效地控制环核苷酸信号传导。我们研究了纹状体中最丰富的PDE10A在纹状体基因调控中的作用，通过评估PDE10A抑制（通过选择性PDE10A抑制剂TP-10）对基因调控的影响，并通过比较完整或多巴胺缺失纹状体中PDE10A mRNA在纹状体中的基本表达与多巴胺激动剂的基因诱导。我们的研究结果表明，PDE10A在感觉运动纹状体中表达最多，在联想纹状体中表达居中，在边缘纹状体中表达较少。抑制PDE10A导致基因表达显著增加，这与局部PDE10A表达水平直接相关。此外，在完整纹状体中，多巴胺耗竭（6-OHDA）后左旋多巴或精神兴奋剂（可卡因、哌甲酯）诱导的基因表达也与局部PDE10A表达水平呈正相关。D1受体和D2受体表达纹状体投射神经元的基因标记均发现了这种关系。总的来说，这些结果表明PDE10A是多巴胺受体相关的第二信使机制的重要组成部分，与纹状体中药物诱导的基因调控密切相关。因此，PDE10A可能作为修饰药物诱导的基因调控和相关神经可塑性的潜在靶点。
Dopamine and other neurotransmitters have the potential to induce neuroplasticity in the striatum via gene regulation. Dopamine receptor-mediated gene regulation relies on second messenger cascades that involve cyclic nucleotides to relay signaling from the synapse to the nucleus. Phosphodiesterases (PDEs) catalyze cyclic nucleotides and thus potently control cyclic nucleotide signaling. We investigated the role of the most abundant striatal PDE, PDE10A, in striatal gene regulation by assessing the effects of PDE10A inhibition (by a selective PDE10A inhibitor, TP-10) on gene regulation and by comparing the basal expression of PDE10A mRNA throughout the striatum with gene induction by dopamine agonists in the intact or dopamine-depleted striatum. Our findings show that PDE10A expression is most abundant in the sensorimotor striatum, intermediate in the associative striatum and lower in the limbic striatum. The inhibition of PDE10A produced pronounced increases in gene expression that were directly related to levels of local PDE10A expression. Moreover, the gene expression induced by L-DOPA after dopamine depletion (by 6-OHDA), or by psychostimulants (cocaine, methylphenidate) in the intact striatum, was also positively correlated with the levels of local PDE10A expression. This relationship was found for gene markers of both D1 receptor- and D2 receptor-expressing striatal projection neurons. Collectively, these results indicate that PDE10A, a vital part of the dopamine receptor-associated second messenger machinery, is tightly linked to drug-induced gene regulation in the striatum. PDE10A may thus serve as a potential target for modifying drug-induced gene regulation and related neuroplasticity.
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影响因子：
6
作者：
Altwal F;Moon C;West AR;Steiner H
通讯作者：
Steiner H
影响因子：
2
作者：
Steiner, H;Gerfen, CR
通讯作者：
Gerfen, CR
DOI：
10.1016/b978-0-12-802206-1.00043-x
发表时间：
2016-01-01
期刊：
HANDBOOK OF BASAL GANGLIA STRUCTURE AND FUNCTION, 2ND EDITION
影响因子：
--
作者：
Cenci, M. A.
通讯作者：
Cenci, M. A.
DOI：
10.1124/jpet.107.132910
发表时间：
2008-05-01
影响因子：
3.5
作者：
Schmidt, C. J.;Chapin, D. S.;Menniti, F. S.
通讯作者：
Menniti, F. S.
影响因子：
4.8
作者：
Kelly, Michy P.;Adamowicz, Wendy;Kleiman, Robin J.
通讯作者：
Kleiman, Robin J.