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首页> 外文学位 >Discovery of a novel role of vasopressin in astrocytes: Vasopressin-induced cytoplasmic and nuclear calcium and kinases signaling cascade and modulation of astrocytes immune function.
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Discovery of a novel role of vasopressin in astrocytes: Vasopressin-induced cytoplasmic and nuclear calcium and kinases signaling cascade and modulation of astrocytes immune function.

机译：血管加压素在星形胶质细胞中的新作用的发现：加压素诱导的细胞质和细胞核钙和激酶信号传导级联和调节星形胶质细胞的免疫功能。

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We sought to determine whether vasopressin V1a receptor (V 1aR) mRNA detected in cortical astrocytes was translated into functional receptors by investigating the effector signaling cascade and gene expression associated with V1aR. Analysis of intracellular Ca2+ ([Ca2+]i) dynamics using the Ca2+ sensitive dyes fura-2 AM and/or fluo-3 AM indicated that exposure of astrocytes to V1 vasopressin receptor agonist (V1 agonist), [Phe 2, Orn8]-oxytocin, induced a marked increase in [Ca 2+]i which was the result of influx of extracellular Ca 2+ and activation of the phosphatidylinositol signaling cascade which releases Ca2+ from endoplasmic reticulum stores. Furthermore, a rapid dynamic translocation of Ca2+ from the cytoplasm to the nucleus occurred in response to V1 agonist. In the pursuit of the downstream consequences of V1aR activation of Ca 2+ signaling, we demonstrated that V1aR activation led to a significant rise in PKC, CaMKII and ERK1/2 activation with CaMKII and ERK1/2 demonstrating dynamic transport between cytoplasmic and nuclear compartments. While no evidence of PKC translocation was apparent, PKC and CaM kinases were required for activation and nuclear translocation of ERK1/2. Subsequent to CaMKII and ERK1/2 translocation to the nucleus, CREB activation occurred and was found to be dependent upon upstream activation of ERK1/2 and CaM kinases. Because astrocytes can exert immune effects analogous to immune cells in the periphery, we further investigated vasopressin regulation of cytokine gene expression in astrocytes. Results from gene array, RT-PCR and ELISA studies indicated that vasopressin dramatically decreased the mRNA and peptide levels of two important pro-inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), suggesting an immunomodulatory function of vasopressin in astrocytes in vitro. This cytokine suppression was dependent on the upstream CREB activation and was demonstrated to be neuroprotective. To our knowledge, this is the first documentation of a vasopressin receptor-induced nuclear Ca2+ signaling and modulation of cytokine gene expression in any cell type. Implications for vasopressin's role in fever, neurodegeneration, autoimmune diseases, stress and neuropsychiatric behaviors are discussed.
机译：我们试图通过研究效应器信号级联和与V相关的基因表达来确定在皮质星形胶质细胞中检测到的血管加压素V 1a 受体（V 1a R）mRNA是否被翻译成功能性受体。 1a R。使用Ca 2 + 敏感染料分析细胞内Ca 2 + （[Ca 2 + ] i ）动力学fura-2 AM和/或fluo-3 AM表示星形胶质细胞暴露于V 1 加压素受体激动剂（V 1 激动剂），[Phe 2 ，Orn 8 ]-催产素引起[Ca 2 + ] i 的显着增加，这是细胞外Ca流入的结果 2 + 和磷脂酰肌醇信号级联的激活，从内质网存储中释放Ca 2 + 。此外，响应V 1 激动剂，Ca 2 + 从细胞质快速动态转移到细胞核。在追求Ca 2 + 信号的V 1a R激活的下游后果中，我们证明了V1aR激活导致PKC，CaMKII和ERK1 / 2的显着增加CaMKII和ERK1 / 2激活表明细胞质和核区室之间的动态运输。虽然没有明显的PKC易位的证据，但PKC和CaM激酶对于ERK1 / 2的激活和核易位是必需的。 CaMKII和ERK1 / 2易位至细胞核后，发生了CREB活化，并发现其依赖于ERK1 / 2和CaM激酶的上游活化。由于星形胶质细胞可以发挥类似于外周免疫细胞的免疫作用，因此我们进一步研究了加压素对星形胶质细胞中细胞因子基因表达的调节。基因阵列，RT-PCR和ELISA研究的结果表明，加压素显着降低了两种重要的促炎细胞因子白介素-1β（IL-1β）和肿瘤坏死因子-α（TNF-α）的mRNA和肽水平，表明加压素在星形胶质细胞中的免疫调节功能这种细胞因子抑制作用取决于上游CREB的激活，并被证明具有神经保护作用。据我们所知，这是血管加压素受体诱导的核Ca 2+ 信号传导和任何细胞类型中细胞因子基因表达调控的第一个文献。讨论了加压素在发烧，神经退行性疾病，自身免疫性疾病，压力和神经精神行为中的作用。

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