Morphine Modulation of Thrombospondin Levels in Astrocytes and Its Implications for Neurite Outgrowth and Synapse Formation
Morphine Modulation of Thrombospondin Levels in Astrocytes and Its Implications for Neurite Outgrowth and Synapse Formation
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DOI：
10.1074/jbc.m110.109827
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发表时间：
2010-12-03
影响因子：
4.8
通讯作者：
Coscia, Carmine J.
中科院分区：
文献类型：
--
作者：
Ikeda, Hiroko;Miyatake, Mayumi;Coscia, Carmine J.
阿片样物质受体通过表皮生长因子受体（EGFR）的反式激活和ERK/MAPK磷酸化的信号启动不同的细胞反应，是细胞类型依赖性。在星形胶质细胞中，存在多种μ阿片受体介导的ERK激活机制，这些机制在时间上是独特的，并且具有不同的结果。在发现慢性阿片类药物治疗的大鼠下调血小板反应蛋白1（TSP 1）的表达，在脑桥核和皮质，我们研究了这种调制星形胶质细胞的作用机制。TSP 1在星形胶质细胞中合成，并释放到细胞外基质中，已知其在突触形成和神经突生长中发挥作用。急性吗啡（小时）减少星形胶质细胞中的TSP 1水平。慢性（天）阿片类药物抑制TSP 1基因表达，并降低其蛋白水平的μ阿片受体和ERK依赖性机制在星形胶质细胞。吗啡也耗尽了由TGF β 1刺激的TSP 1水平，并消除了由该因子诱导的ERK激活。星形胶质细胞-神经元共培养物的慢性吗啡处理减少了神经突生长和突触形成。因此，急性和慢性治疗后检测到吗啡的抑制作用。通过功能阻断TSP 1抗体抑制吗啡对ERK的激活，提出了吗啡对ERK信号传导的急性机制，该机制需要TSP 1水平的耗尽。这提出了一种新的可能性，即急性吗啡使用TSP 1作为EGF样配体的来源来激活EGFR。TSP 1的慢性吗啡抑制使人想起μ阿片类药物通过磷酸化ERK反馈抑制机制对EGFR诱导的星形胶质细胞增殖的负面影响。经典EGFR反式激活的这两种变化可能使阿片类药物减少神经突生长和突触形成。
Opioid receptor signaling via EGF receptor (EGFR) transactivation and ERK/MAPK phosphorylation initiates diverse cellular responses that are cell type-dependent. In astrocytes, multiple mu opioid receptor-mediated mechanisms of ERK activation exist that are temporally distinctive and feature different outcomes. Upon discovering that chronic opiate treatment of rats down-regulates thrombospondin 1 (TSP1) expression in the nucleus accumbens and cortex, we investigated the mechanism of action of this modulation in astrocytes. TSP1 is synthesized in astrocytes and is released into the extracellular matrix where it is known to play a role in synapse formation and neurite outgrowth. Acute morphine (hours) reduced TSP1 levels in astrocytes. Chronic (days) opioids repressed TSP1 gene expression and reduced its protein levels by mu opioid receptor and ERK-dependent mechanisms in astrocytes. Morphine also depleted TSP1 levels stimulated by TGF beta 1 and abolished ERK activation induced by this factor. Chronic morphine treatment of astrocyte-neuron co-cultures reduced neurite outgrowth and synapse formation. Therefore, inhibitory actions of morphine were detected after both acute and chronic treatments. An acute mechanism of morphine signaling to ERK that entails depletion of TSP1 levels was suggested by inhibition of morphine activation of ERK by a function-blocking TSP1 antibody. This raises the novel possibility that acute morphine uses TSP1 as a source of EGF-like ligands to activate EGFR. Chronic morphine inhibition of TSP1 is reminiscent of the negative effect of mu opioids on EGFR-induced astrocyte proliferation via a phospho-ERK feedback inhibition mechanism. Both of these variations of classical EGFR transactivation may enable opiates to diminish neurite outgrowth and synapse formation.