Norepinephrine induces rapid and long-lasting phosphorylation and redistribution of connexin 43 in cortical astrocytes
Norepinephrine induces rapid and long-lasting phosphorylation and redistribution of connexin 43 in cortical astrocytes
复制标题
去甲肾上腺素诱导皮质星形胶质细胞中连接蛋白 43 的快速且持久的磷酸化和重新分布
DOI：
10.1016/j.bbrc.2018.09.021
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发表时间：
2018
影响因子：
3.1
通讯作者：
Yasui Masato
中科院分区：
文献类型：
--
作者：
Nuriya Mutsuo;Morita Ayaka;Shinotsuka Takanori;Yamada Tomoko;Yasui Masato
去甲肾上腺素（NE）调节大脑功能取决于内部和外部环境。虽然NE的神经调节作用已得到很好的表征，但皮质星形胶质细胞对生理去甲肾上腺素能系统的反应和参与在很大程度上仍然未知，特别是在分子水平上。在这项研究中，我们的生化特性的行动NE对星形胶质细胞的小鼠新皮层。在幼年和青春期动物的脑切片中，NE刺激急性脑切片会迅速增加连接蛋白43（Cx43）在丝氨酸（Ser）368处的磷酸化。磷酸化由α 1-肾上腺素能受体下的蛋白激酶C（PKC）途径介导，并在短暂暴露于NE后数十分钟内保持升高，在细胞内钙水平恢复正常水平后很久，表明这种磷酸化事件的可塑性。重要的是，这种磷酸化事件持续存在的神经元传输的情况下，表明NE对Cx43磷酸化的影响是直接诱导星形胶质细胞。此外，这些NE诱导的磷酸化与Cx43从缝隙连接斑块到非连接区室的生化解离有关。最后，我们表明，去甲肾上腺素能系统使用精神活性药物的药理学操作调制Cx43的磷酸化在体内大脑皮质。这些数据表明，NE直接作用于星形胶质细胞与神经元平行，并以可塑性方式调节功能关键的连接蛋白通道蛋白。因此，由NE的"胶质调节"作用诱导的星形胶质细胞的可塑性可能在其脑中的生理和药理作用中发挥重要作用。
Norepinephrine (NE) modulates brain functions depending on both the internal and external environment. While the neuromodulatory actions of NE have been well characterized, the response and involvement of cortical astrocytes to physiological noradrenergic systems remain largely unknown, especially at the molecular level. In this study, we biochemically characterize the action of NE on astrocytes of the murine neocortex. NE stimulation of acute brain slices rapidly increase phosphorylation of connexin 43 (Cx43) at Serine (Ser) 368, in slices from both juvenile and adolescent animals. The phosphorylation is mediated by the protein kinase C (PKC) pathway under the α1-adrenergic receptor and remains elevated for tens of minutes following brief exposure to NE, well after the intracellular calcium level returns to normal level, suggesting the plastic nature of this phosphorylation event. Importantly, this phosphorylation event persists in the absence of neuronal transmissions, suggesting that the effect of NE on Cx43 phosphorylation is induced directly on astrocytes. Furthermore, these NE-induced phosphorylations are associated with biochemical dissociation of Cx43 from gap-junctional plaques to non-junctional compartments. Finally, we show that pharmacological manipulation of the noradrenergic system using psychoactive drugs modulates phosphorylation of Cx43 in the cerebral cortexin vivo. These data suggest that NE acts directly on astrocytes in parallel with neurons and modulates functionally critical connexin channel proteins in a plastic manner. Thus, plasticity of astrocytes induced by the “gliomodulatory” actions of NE may play important roles in their physiological as well as pharmacological actions in the brain.