Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes.
Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes.
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DOI：
10.1016/j.neuropharm.2014.06.011
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发表时间：
2014-10
影响因子：
4.7
通讯作者：
Ghorpade A
中科院分区：
文献类型：
--
作者：
Cisneros IE;Ghorpade A
约5%的美国人口滥用甲基苯丙胺，约10-15%的人类免疫缺陷病毒-1（HIV-1）患者报告使用甲基苯丙胺。甲基苯丙胺滥用加速艾滋病毒相关的神经认知障碍（HAND）和星形胶质细胞诱导的神经毒性的发作和严重程度。METH激活G蛋白偶联受体，如痕量胺相关受体1（TAAR 1），增加单胺能系统突触前细胞中的细胞内环磷酸腺苷（cAMP）水平。在本研究中，我们研究了METH和HIV-1对原代人星形胶质细胞TAAR 1表达、功能和谷氨酸清除的影响。我们的研究结果表明，组合条件增加TAAR 1 mRNA水平7倍，并增加细胞内cAMP水平。METH和β-苯乙胺（β-PEA），已知的TAAR 1激动剂，增加星形胶质细胞中的细胞内cAMP水平。此外，TAAR 1敲低显著降低了细胞内cAMP水平，表明通过星形胶质细胞TAAR 1进行信号传导。METH +/− HIV-1降低兴奋性氨基酸转运蛋白-2（EAAT-2）mRNA，并显著降低谷氨酸清除率。RNA干扰TAAR 1阻止了METH介导的EAAT-2减少。TAAR 1敲除显著增加谷氨酸清除率，METH进一步显著提高谷氨酸清除率。此外，TAAR 1过表达显著降低EAAT-2水平和谷氨酸清除率，METH进一步降低了EAAT-2水平和谷氨酸清除率。总之，我们的数据表明，METH处理激活TAAR 1，导致人星形胶质细胞中的细胞内cAMP，并调节谷氨酸清除能力。此外，星形胶质细胞TAAR 1水平的分子变化对应于星形胶质细胞EAAT-2水平和功能的变化。据我们所知，这是第一份报告，涉及星形胶质细胞TAAR 1作为一种新的受体甲基在联合损伤的背景下，手。
Methamphetamine (METH) is abused by about 5% of the United States population with approximately 10–15% of human immunodeficiency virus-1 (HIV-1) patients reporting its use. METH abuse accelerates the onset and severity of HIV-associated neurocognitive disorders (HAND) and astrocyte-induced neurotoxicity. METH activates G-protein coupled receptors such as trace amine associated receptor 1 (TAAR1) increasing intracellular cyclic adenosine monophosphate (cAMP) levels in presynaptic cells of monoaminergic systems. In the present study, we investigated the effects of METH and HIV-1 on primary human astrocyte TAAR1 expression, function and glutamate clearance. Our results demonstrate combined conditions increased TAAR1 mRNA levels 7-fold and increased intracellular cAMP levels. METH and beta-phenylethylamine (β-PEA), known TAAR1 agonists, increased intracellular cAMP levels in astrocytes. Further, TAAR1 knockdown significantly reduced intracellular cAMP levels in response to METH/β-PEA, indicating signaling through astrocyte TAAR1. METH +/− HIV-1 decreased excitatory amino acid transporter-2 (EAAT-2) mRNA and significantly decreased glutamate clearance. RNA interference for TAAR1 prevented METH-mediated decreases in EAAT-2. TAAR1 knockdown significantly increased glutamate clearance, which was further heightened significantly by METH. Moreover, TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance that were further reduced by METH. Taken together, our data show that METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function. To our knowledge this is the first report implicating astrocyte TAAR1 as a novel receptor for METH during combined injury in the context of HAND.
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影响因子：
1
作者：
Cisneros IE;Ghorpade A
通讯作者：
Ghorpade A
安非他明、3,4-亚甲二氧基甲基苯丙胺、麦角酸二乙酰胺和儿茶酚胺神经递质的代谢物是大鼠微量胺受体的激动剂
影响因子：
3.6
作者：
Bunzow, JR;Sonders, MS;Grandy, DK
通讯作者：
Grandy, DK
影响因子：
6.4
作者：
Ellis, RJ;Childers, ME;Grant, I
通讯作者：
Grant, I
影响因子：
6.2
作者：
FRASER, DD;MUDRICKDONNON, LA;MACVICAR, BA
通讯作者：
MACVICAR, BA
影响因子：
4.7
作者：
Gochenauer, GE;Robinson, MB
通讯作者：
Robinson, MB