Dopamine D1 receptor signaling system regulates ryanodine receptor expression after intermittent exposure to methamphetamine in primary cultures of midbrain and cerebral cortical neurons
Dopamine D1 receptor signaling system regulates ryanodine receptor expression after intermittent exposure to methamphetamine in primary cultures of midbrain and cerebral cortical neurons
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DOI：
10.1111/j.1471-4159.2011.07366.x
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发表时间：
2011-09-01
影响因子：
4.7
通讯作者：
Ohkuma, Seitaro
中科院分区：
文献类型：
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作者：
Kurokawa, Kazuhiro;Mizuno, Koji;Ohkuma, Seitaro
尽管有报道甲基苯丙胺 (METH) 可以上调小鼠大脑中的 RyR，但兰尼碱受体 (RyR) 表达的调节机制尚不清楚。本研究使用间歇性暴露于 METH 和多巴胺受体 (DR) 激动剂（每天 1 小时，持续 3 天）的原代培养物中的中脑和大脑皮层神经元，研究多巴胺能系统对 RyR 表达的调节机制。间歇性的冰毒 (10 μM) 暴露增强了两种类型神经元中 RyR-1 和 -2 蛋白及其 mRNA 的表达，但没有增强 RyR-3 的表达。这些 METH 诱导的 RyR 蛋白及其 mRNA 的增加被 SCH23390（一种选择性 D1DR 拮抗剂）剂量依赖性地阻断，但不是 D2DR 拮抗剂舒必利，这表明 D(1)DR 在这些神经元中 METH 的 RyR 表达中具有调节作用。在大脑皮层神经元中，间歇性暴露于 SKF82958（一种选择性 D1DR 激动剂）会增加 RyR-1 和 -2 蛋白及其 mRNA，而喹吡罗（一种选择性 D2DR 激动剂）则没有效果。 KT5720 是一种蛋白激酶 A 抑制剂，可剂量依赖性地减弱 METH 刺激的大脑皮层神经元中 RyR-1 和 -2 的表达。 METH 显着增加 cAMP 反应元件结合蛋白的磷酸化，而 SCH23390 完全抑制该磷酸化。这些结果表明 RyR-1 和 -2 表达由 D(1)DR 通过与 D(1)DR 连接的信号转导来调节。
Regulatory mechanisms of ryanodine receptor (RyR) expression are not well known, although methamphetamine (METH) has been reported to up-regulate RyRs in mouse brain. This study investigate regulatory mechanisms of RyR expression by dopaminergic system using the midbrain and cerebral cortical neurons in primary culture intermittently exposed to METH and dopamine receptor (DR) agonists (1 h/day, for 3 days). Intermittent METH (10 mu M) exposure enhanced RyR-1 and -2 proteins and their mRNA, but not RyR-3 expression in the both types of the neurons. These METH-induced increases of RyR proteins and their mRNA were dose-dependently blocked by SCH23390 (a selective D1DR antagonist), but not a D2DR antagonist sulpiride, suggesting a regulatory role of D(1)DRs in RyR expression by METH in these neurons. In cerebral cortical neurons, intermittent SKF82958 (a selective D1DR agonist) exposure increased RyR-1 and -2 proteins and their mRNA, whereas quinpirole (a selective D2DR agonist) showed no effects. KT5720, a protein kinase A inhibitor, dose-dependently attenuated the METH-stimulated RyR-1 and -2 expressions in cerebral cortical neurons. METH significantly increased phosphorylation of cAMP-response element-binding protein, which was completely suppressed by SCH23390. These results indicate that RyR-1 and -2 expressions are regulated by D(1)DRs via the signal transduction linked to D(1)DRs.