Alterations of CXCR4 function in μ-opioid receptor-deficient glia.
Alterations of CXCR4 function in μ-opioid receptor-deficient glia.
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DOI：
10.1111/j.1460-9568.2010.07402.x
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发表时间：
2010-10
期刊：
影响因子：
--
通讯作者：
Meucci O
中科院分区：
文献类型：
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作者：
Burbassi S;Sengupta R;Meucci O
趋化因子受体 CXCR4 和 μ-阿片受体 (MOR) 是 G 蛋白偶联受体 (GPCR)，对于神经和免疫系统的正常功能至关重要。多项研究表明，MOR 是大脑中 CXCR4 的关键调节因子。然而，阿片类药物/趋化因子相互作用的分子基础尚未完全了解，并且可能涉及神经元和神经胶质细胞中的不同机制。我们之前的研究表明，MOR 刺激特异性上调神经元中的蛋白质铁蛋白重链 (FHC)（CXCR4 的抑制剂），并表明其他机制可能在神经胶质细胞中发挥作用。在这项研究中，我们研究了缺乏 MOR 的大脑和星形胶质细胞培养物中 CXCR4 的功能。与野生型 (WT) 对照相比，MOR−/− 小鼠的脑切片和组织匀浆中发现 CXCR4 与 G 蛋白的偶联减少。对 CXCR4 下游靶标（Akt 和 ERK1/2）的分析表明，MOR−/− 小鼠的神经胶质培养物中 CXCR4 诱导的信号传导也有所减少。 δ-阿片受体 (DOR) 特异性配体的药理学研究表明，DOR-CXCR4 相互作用与体外和体内 MOR 缺陷细胞中 CXCR4 的抑制有关。此外，在 MOR−/− 小鼠的脑组织和培养的神经胶质细胞中发现 CXCR4/DOR 免疫共沉淀增加。重要的是，CXCR4 功能通过 DOR 拮抗剂预处理得以恢复。总的来说，这些发现表明 DOR 在神经胶质细胞中 CXCR4 的调节中发挥着至关重要的作用，可能是通过沉默受体异二聚体。数据还表明，阿片系统以不同的方式干扰正常的 CXCR4 功能，具体取决于受体亚型。
The chemokine receptor CXCR4 and the μ-opioid receptor (MOR) are G-protein–coupled receptors (GPCRs) essential to normal function of the nervous and immune systems. Several studies suggest that MOR is a key regulator of CXCR4 in the brain; however, the molecular basis of the opioid/chemokine interaction are not fully understood and may involve different mechanisms in neuronal and glial cells. Our previous studies demonstrated that MOR stimulation specifically up-regulates the protein ferritin heavy chain (FHC) - an inhibitor of CXCR4 - in neurons and suggested additional mechanisms could be operative in glial cells. In this study, we investigated CXCR4 function in brains and astroglia cultures deprived of MOR. Reduced coupling of CXCR4 to G proteins was found in brain slices and tissue homogenates of MOR−/− mice compared to wild type (WT) controls. CXCR4-induced signaling was also reduced in glial cultures from MOR−/− mice, as shown by analysis of CXCR4 downstream targets (Akt and ERK1/2). Pharmacological studies with δ-opioid receptor (DOR)-specific ligands suggested that DOR-CXCR4 interactions are implicated in the inhibition of CXCR4 in MOR-deficient cells both in vitro and in vivo. Moreover, increased CXCR4/DOR co-immunoprecipitation was found in brain tissue and cultured glia from MOR−/− mice. Importantly, CXCR4 function was restored by pretreatment with a DOR antagonist. Overall, these findings indicate that DOR play a crucial role in the regulation of CXCR4 in glia, likely via silent receptor heterodimers. The data also suggest that the opiate system interferes with normal CXCR4 function in different ways and depending on receptor subtypes.