Prenatal cocaine exposure increases synaptic localization of a neuronal RasGEF, GRASP-1 via hyperphosphorylation of AMPAR anchoring protein, GRIP.
Prenatal cocaine exposure increases synaptic localization of a neuronal RasGEF, GRASP-1 via hyperphosphorylation of AMPAR anchoring protein, GRIP.
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DOI：
10.1371/journal.pone.0025019
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Wang HY
中科院分区：
文献类型：
--
作者：
Bakshi K;Kosciuk M;Nagele RG;Friedman E;Wang HY
产前可卡因暴露导致突触锚定蛋白、谷氨酸受体相互作用蛋白（GRIP 1/2）的持续磷酸化，阻止含GluR 2/3的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸型谷氨酸受体的突触靶向（AMPAR; J. Neurosci. 29：6308-6319，2009）。由于GRIP相关神经元rasGEF蛋白（GRASP-1）的过表达特异性地降低了AMPAR的突触靶向，我们假设产前可卡因暴露增强了GRASP-1突触膜定位，导致ras家族蛋白的过度激活和肌动蛋白聚合的增强。我们的研究结果表明，显着增加GRIP 1相关的GRASP-1的含量，其rasGEF活性减少约40%，在额叶皮质（FCX）的21日龄（P21）产前可卡因暴露大鼠。这种可卡因效应是持续的蛋白激酶C（PKC）和下游Src酪氨酸激酶介导的GRIP磷酸化的结果。过度活化的PKC也增加膜相关的GRASP-1和激活小G蛋白RhoA，cdc 42/Rac 1和Rap 1以及丝状肌动蛋白（F-肌动蛋白）水平，而不影响肌动蛋白的磷酸化状态。由于增加F-肌动蛋白促进蛋白质转运，我们的研究结果表明，增加GRASP-1突触定位在产前可卡因暴露的大脑是一种适应性反应，恢复AMPA-GluR 2/3的突触表达。我们早期的数据表明，持续的PKC介导的GRIP磷酸化减少了产前可卡因暴露的大脑中GluR 2/3突触靶向，我们现在表明，增加GRIP相关的GRASP-1可能有助于减少GluR 2/3突触表达和AMPAR信号转导缺陷。
Prenatal cocaine exposure causes sustained phosphorylation of the synaptic anchoring protein, glutamate receptor interacting protein (GRIP1/2), preventing synaptic targeting of the GluR2/3-containing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs; J. Neurosci. 29: 6308–6319, 2009). Because overexpression of GRIP-associated neuronal rasGEF protein (GRASP-1) specifically reduces the synaptic targeting of AMPARs, we hypothesized that prenatal cocaine exposure enhances GRASP-1 synaptic membrane localization leading to hyper-activation of ras family proteins and heightened actin polymerization. Our results show a markedly increased GRIP1-associated GRASP-1 content with approximately 40% reduction in its rasGEF activity in frontal cortices (FCX) of 21-day-old (P21) prenatal cocaine-exposed rats. This cocaine effect is the result of a persistent protein kinase C (PKC)- and downstream Src tyrosine kinase-mediated GRIP phosphorylation. The hyperactivated PKC also increased membrane-associated GRASP-1 and activated small G-proteins RhoA, cdc42/Rac1 and Rap1 as well as filamentous actin (F-actin) levels without an effect on the phosphorylation state of actin. Since increased F-actin facilitates protein transport, our results suggest that increased GRASP-1 synaptic localization in prenatal cocaine-exposed brains is an adaptive response to restoring the synaptic expression of AMPA-GluR2/3. Our earlier data demonstrated that persistent PKC-mediated GRIP phosphorylation reduces GluR2/3 synaptic targeting in prenatal cocaine-exposed brains, we now show that the increased GRIP-associated GRASP-1 may contribute to the reduction in GluR2/3 synaptic expression and AMPAR signaling defects.
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影响因子：
25
作者：
Hoogenraad, CC;Milstein, AD;Sheng, M
通讯作者：
Sheng, M
影响因子：
1.9
作者：
Huentelman, Matthew J.;Stephan, Dietrich A.;Talboom, Joshua;Corneveaux, Jason J.;Reiman, David A.;Gerber, Jill D.;Barnes, Carol A.;Alexander, Gene E.;Reiman, Eric M.;Bimonte-Nelson, Heather A.
通讯作者：
Bimonte-Nelson, Heather A.
DOI：
10.1073/pnas.0908563106
发表时间：
2009-10-20
影响因子：
11.1
作者：
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通讯作者：
Arnsten, Amy F. T.
影响因子：
4.2
作者：
Brennan, Avis R.;Yuan, Peixiong;Arnsten, Amy F. T.
通讯作者：
Arnsten, Amy F. T.
影响因子：
4.7
作者：
Fu, Zhanyan;Lee, Sang Hyoung;Pak, Daniel T. S.
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Pak, Daniel T. S.