Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) controls activation of extracellular signal-regulated kinase (ERK) signaling in the striatum and long-term behavioral responses to cocaine.
Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) controls activation of extracellular signal-regulated kinase (ERK) signaling in the striatum and long-term behavioral responses to cocaine.
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DOI：
10.1016/j.biopsych.2009.03.014
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发表时间：
2009-10-15
影响因子：
10.6
通讯作者：
Brambilla R
中科院分区：
文献类型：
--
作者：
Fasano S;D'Antoni A;Orban PC;Valjent E;Putignano E;Vara H;Pizzorusso T;Giustetto M;Yoon B;Soloway P;Maldonado R;Caboche J;Brambilla R
Ras-细胞外信号调节激酶（Ras-ERK）信号传导是认知功能的分子机制的核心。在纹状体中，ERK 1/2激酶被谷氨酸和多巴胺D1/5受体共激活，但提供这种信号整合的机制仍然未知。Ras-鸟嘌呤核苷酸释放因子1（Ras-GRF 1）是Ras-ERK信号传导的神经元特异性激活剂，是将这些神经递质信号与纹状体黑质中棘神经元（MSN）中的ERK激酶偶联以及调节对药物滥用（如可卡因）的行为反应的可能候选者。我们使用Ras-GRF 1基因修饰的小鼠突变体作为原代MSN培养物和器官型切片的来源，对谷氨酸和多巴胺受体激动剂进行免疫印迹和免疫荧光研究。在用可卡因治疗后，还对小鼠进行了行为和免疫组织化学研究。磷酸化的ERK 1/2响应谷氨酸，多巴胺D1激动剂，或同时两种刺激是受损的Ras-GRF 1缺陷的纹状体细胞和纹状体黑质MSN室的器官型切片。一致的是，可卡因的行为反应也受到影响，在Ras-GRF 1缺陷或过表达的小鼠。运动敏化和条件性位置偏爱在Ras-GRF 1缺陷的小鼠显着减弱，而一个强大的易化在过表达的转基因动物观察。最后，我们在这些动物的MSN中发现了ERK 1/2激活和FosB/ΔFosB积累的相应变化，FosB/Δ FosB是对可卡因长期反应的一个良好表征的标志物。这些结果强烈暗示Ras-GRF 1在整合两个主要的神经递质输入纹状体和适应不良的调制纹状体网络响应可卡因。
Ras-extracellular signal-regulated kinase (Ras-ERK) signaling is central to the molecular machinery underlying cognitive functions. In the striatum, ERK1/2 kinases are co-activated by glutamate and dopamine D1/5 receptors, but the mechanisms providing such signaling integration are still unknown. The Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal specific activator of Ras-ERK signaling, is a likely candidate for coupling these neurotransmitter signals to ERK kinases in the striatonigral medium spiny neurons (MSN) and for modulating behavioral responses to drug abuse such as cocaine. We used genetically modified mouse mutants for Ras-GRF1 as a source of primary MSN cultures and organotypic slices, to perform both immunoblot and immunofluorescence studies in response to glutamate and dopamine receptor agonists. Mice were also subjected to behavioral and immunohistochemical investigations upon treatment with cocaine. Phosphorylation of ERK1/2 in response to glutamate, dopamine D1 agonist, or both stimuli simultaneously is impaired in Ras-GRF1– deficient striatal cells and organotypic slices of the striatonigral MSN compartment. Consistently, behavioral responses to cocaine are also affected in mice deficient for Ras-GRF1 or overexpressing it. Both locomotor sensitization and conditioned place preference are significantly attenuated in Ras-GRF1– deficient mice, whereas a robust facilitation is observed in overexpressing transgenic animals. Finally, we found corresponding changes in ERK1/2 activation and in accumulation of FosB/ΔFosB, a well-characterized marker for long-term responses to cocaine, in MSN from these animals. These results strongly implicate Ras-GRF1 in the integration of the two main neurotransmitter inputs to the striatum and in the maladaptive modulation of striatal networks in response to cocaine.
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影响因子：
4.3
作者：
Fernandez E;Schiappa R;Girault JA;Le Novère N
通讯作者：
Le Novère N
影响因子：
4.7
作者：
Chen, Pei-Chun;Lao, Chu-Lan;Chen, Jin-Chung
通讯作者：
Chen, Jin-Chung
影响因子：
7.6
作者：
Ferguson, Susan M.;Fasano, Stefania;Robinson, Terry E.
通讯作者：
Robinson, Terry E.
DOI：
10.2174/1566524023362005
发表时间：
2002-11-01
期刊：
Current Molecular Medicine (Hilversum)
影响因子：
--
作者：
Fasano, S.;Brambilla, R.
通讯作者：
Brambilla, R.
影响因子：
5.3
作者：
Brami-Cherrier, K;Valjent, E;Caboche, J
通讯作者：
Caboche, J