Methamphetamine Activates Trace Amine Associated Receptor 1 to Regulate Astrocyte Excitatory Amino Acid Transporter-2 via Differential CREB Phosphorylation During HIV-Associated Neurocognitive Disorders.
Methamphetamine Activates Trace Amine Associated Receptor 1 to Regulate Astrocyte Excitatory Amino Acid Transporter-2 via Differential CREB Phosphorylation During HIV-Associated Neurocognitive Disorders.
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DOI：
10.3389/fneur.2020.593146
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发表时间：
2020
影响因子：
3.4
通讯作者：
Borgmann K
中科院分区：
文献类型：
--
作者：
Cisneros IE;Ghorpade A;Borgmann K
甲基苯丙胺（METH）的使用，被称为甲基苯丙胺使用障碍（MUD），导致神经认知能力下降，这是与艾滋病毒相关的神经认知障碍（HAND）共有的特征。MUD部分通过谷氨酸失调加剧HAND。星形胶质细胞兴奋性氨基酸转运蛋白(EAAT)-2负责突触环境中90%的谷氨酸摄取，并且在甲基苯丙胺和HIV-1中显著降低。我们之前的研究表明星形胶质细胞微量胺相关受体（TAAR） 1参与了EAAT-2的调控。星形胶质细胞EAAT-2在转录水平上受cAMP响应元件结合蛋白（CREB）和NF-κB、cAMP、钙和IL-1β激活的转录因子调控。第二信使，cAMP和钙，是由TAAR1激活触发的，而TAAR1被IL-1β上调，meth介导的这些第二信使和信号转导途径的增加并未被证明直接降低星形胶质细胞EAAT-2。我们提出CREB激活作为EAAT-2转录的主调控因子，在甲基醚诱导的TAAR1激活的下游。为了研究CREB激活事件的时间顺序，基因编码的钙指标GCaMP6s被用来可视化甲基甲醚诱导的人类星形胶质细胞钙信号。RNA干扰和靶向或阻断camp依赖性蛋白激酶A和钙/钙调蛋白激酶II的药物抑制剂证实了甲基甲醚诱导的EAAT-2调节和由此产生的谷氨酸清除。此外，我们研究了甲基甲醚介导的CREB在丝氨酸133和142位点的磷酸化，分别是共激活物和共抑制物形式。总的来说，这项工作揭示了甲基醚诱导的CREB差异磷酸化是EAAT-2功能的关键调节因子，因此可能是HAND背景下甲基醚诱导的兴奋性毒性衰减的机制靶点。
Methamphetamine (METH) use, referred to as methamphetamine use disorder (MUD), results in neurocognitive decline, a characteristic shared with HIV-associated neurocognitive disorders (HAND). MUD exacerbates HAND partly through glutamate dysregulation. Astrocyte excitatory amino acid transporter (EAAT)-2 is responsible for >90% of glutamate uptake from the synaptic environment and is significantly decreased with METH and HIV-1. Our previous work demonstrated astrocyte trace amine associated receptor (TAAR) 1 to be involved in EAAT-2 regulation. Astrocyte EAAT-2 is regulated at the transcriptional level by cAMP responsive element binding (CREB) protein and NF-κB, transcription factors activated by cAMP, calcium and IL-1β. Second messengers, cAMP and calcium, are triggered by TAAR1 activation, which is upregulated by IL-1β METH-mediated increases in these second messengers and signal transduction pathways have not been shown to directly decrease astrocyte EAAT-2. We propose CREB activation serves as a master regulator of EAAT-2 transcription, downstream of METH-induced TAAR1 activation. To investigate the temporal order of events culminating in CREB activation, genetically encoded calcium indicators, GCaMP6s, were used to visualize METH-induced calcium signaling in primary human astrocytes. RNA interference and pharmacological inhibitors targeting or blocking cAMP-dependent protein kinase A and calcium/calmodulin kinase II confirmed METH-induced regulation of EAAT-2 and resultant glutamate clearance. Furthermore, we investigated METH-mediated CREB phosphorylation at both serine 133 and 142, the co-activator and co-repressor forms, respectively. Overall, this work revealed METH-induced differential CREB phosphorylation is a critical regulator for EAAT-2 function and may thus serve as a mechanistic target for the attenuation of METH-induced excitotoxicity in the context of HAND.
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影响因子：
1
作者：
Cisneros IE;Ghorpade A
通讯作者：
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影响因子：
4.7
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影响因子：
7.6
作者：
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通讯作者：
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影响因子：
4.7
作者：
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影响因子：
2.9
作者：
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