Mechanisms Regulating the Association of Protein Phosphatase 1 with Spinophilin and Neurabin.
Mechanisms Regulating the Association of Protein Phosphatase 1 with Spinophilin and Neurabin.
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DOI：
10.1021/acschemneuro.8b00144
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发表时间：
2018-11-21
影响因子：
5
通讯作者：
Baucum AJ 2nd
中科院分区：
文献类型：
--
作者：
Edler MC;Salek AB;Watkins DS;Kaur H;Morris CW;Yamamoto BK;Baucum AJ 2nd
蛋白质磷酸化是信号转导的关键介质，允许底物活性的动态调节。而蛋白激酶通过靶向特定的氨基酸序列获得底物特异性，丝氨酸/苏氨酸磷酸酶催化亚基在脱磷酸化底物的能力上更加混乱。为了获得底物特异性，丝氨酸/苏氨酸磷酸酶利用靶向蛋白调节磷酸酶的亚细胞定位和催化活性。嗜spinophin及其同源物neurabin是两种最丰富的树突棘定位蛋白磷酸酶1 （PP1）靶向蛋白。在帕金森病（PD）动物模型的纹状体中，嗜脊髓蛋白和PP1之间的关联增加。然而，调节嗜脊髓素和神经素与PP1关联的机制尚不清楚。在这里，我们报道了在异源细胞系统中，通过CDK5的表达和激活，嗜脊髓蛋白和PP1α或PP1γ1之间的关联增加。这种增加的关联至少部分是由于PP1的磷酸化。相反，CDK5的表达和激活降低了PP1与神经素的关联。与多巴胺消耗一样，甲基苯丙胺（冰毒）滥用会导致多巴胺信号的持续改变，从而影响纹状体中棘神经元的功能和生物化学。此外，甲基苯丙胺毒性和多巴胺耗竭都与运动控制和运动学习缺陷有关。病理学上，我们观察到在暴食冰毒一个月后，大鼠纹状体中嗜脊髓蛋白与PP1的相关性降低。行为学上，我们发现嗜脊髓蛋白的缺失再现了先前在多巴胺耗尽和冰毒治疗的动物中观察到的轮状体病理。总之，这些数据对与多巴胺信号改变相关的多种疾病状态（如PD和精神兴奋剂药物滥用）具有启示意义，并描绘了PP1与嗜脊髓蛋白和神经素的相互作用可能受到差异调节的新机制。
Protein phosphorylation is a key mediator of signal transduction, allowing for dynamic regulation of substrate activity. Whereas protein kinases obtain substrate specificity by targeting specific amino acid sequences, serine/threonine phosphatase catalytic subunits are much more promiscuous in their ability to dephosphorylate substrates. To obtain substrate specificity, serine/threonine phosphatases utilize targeting proteins to regulate phosphatase subcellular localization and catalytic activity. Spinophilin and its homologue neurabin are two of the most abundant dendritic spine-localized protein phosphatase 1 (PP1) targeting proteins. The association between spinophilin and PP1 is increased in the striatum of animal models of Parkinson’s disease (PD). However, mechanisms that regulate the association of spinophilin and neurabin with PP1 are unclear. Here, we report that the association between spinophilin and PP1α or PP1γ1 was increased by CDK5 expression and activation in a heterologous cell system. This increased association is at least partially due to phosphorylation of PP1. Conversely, CDK5 expression and activation decreased the association of PP1 with neurabin. As with dopamine depletion, methamphetamine (METH) abuse causes persistent alterations in dopamine signaling which influence striatal medium spiny neuron function and biochemistry. Moreover, both METH toxicity and dopamine depletion are associated with deficits in motor control and motor learning. Pathologically, we observed a decreased association of spinophilin with PP1 in rat striatum evaluated one month following a binge METH paradigm. Behaviorally, we found that loss of spinophilin recapitulates rotarod pathology previously observed in dopamine-depleted and METH-treated animals. Together, these data have implications in multiple disease states associated with altered dopamine signaling such as PD and psychostimulant drug abuse and delineate a novel mechanism by which PP1 interactions with spinophilin and neurabin may be differentially regulated.
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影响因子：
64.8
作者：
Banks, Alexander S.;McAllister, Fiona E.;Camporez, Joao Paulo G.;Zushin, Peter-James H.;Jurczak, Michael J.;Laznik-Bogoslavski, Dina;Shulman, Gerald I.;Gygi, Steven P.;Spiegelman, Bruce M.
通讯作者：
Spiegelman, Bruce M.
影响因子：
2.9
作者：
Hsieh-Wilson, LC;Allen, PB;Greengard, P
通讯作者：
Greengard, P
影响因子：
4.8
作者：
Hsieh-Wilson, LC;Benfenati, F;Greengard, P
通讯作者：
Greengard, P
影响因子：
7
作者：
Baucum, Anthony J., II;Jalan-Sakrikar, Nidhi;Colbran, Roger J.
通讯作者：
Colbran, Roger J.
影响因子：
4.8
作者：
Carmody, Leigh C.;Baucum, Anthony J., II;Colbran, Roger J.
通讯作者：
Colbran, Roger J.