Activation of 5-HT2A/C receptors counteracts 5-HT1A regulation of n-methyl-D-aspartate receptor channels in pyramidal neurons of prefrontal cortex.
Activation of 5-HT2A/C receptors counteracts 5-HT1A regulation of n-methyl-D-aspartate receptor channels in pyramidal neurons of prefrontal cortex.
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DOI：
10.1074/jbc.m801713200
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发表时间：
2008-06-20
期刊：
影响因子：
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通讯作者：
Yan Z
中科院分区：
文献类型：
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作者：
Yuen EY;Jiang Q;Chen P;Feng J;Yan Z
前额皮质（PFC）中异常的血清素-谷氨酸相互作用与许多精神疾病的病理生理学有关，包括精神分裂症和抑郁症。然而，这种相互作用发生的机制仍不清楚。我们之前的研究表明，5-HT1A 受体的激活通过破坏基于微管的 NMDAR 运输来抑制 PFC 锥体神经元中的 N-甲基-d-天冬氨酸 (NMDA) 受体 (NMDAR) 电流。在这里，我们发现5-HT2A/C受体的激活显着减弱了5-HT1A对NMDAR电流和微管解聚的影响。在用各种 5-HT 相关药物治疗的完整动物的 PFC 锥体神经元中也观察到 5-HT2A/C 对 5-HT1A 突触 NMDAR 反应调节的反作用。此外，5-HT2A/C 刺激触发了树突状过程中细胞外信号调节激酶 (ERK) 的激活。抑制 β-arrestin/Src/dynamin 信号传导可阻断 5-HT2A/C 对 ERK 的激活以及 5-HT2A/C 对 NMDAR 电流的 5-HT1A 调节的反作用。免疫细胞化学研究表明，5-HT2A/C 处理阻断了 5-HT1A 对树突表面 NR2B 簇的抑制作用，而细胞敲低 β-arrestins 可以阻止这种作用。综上所述，我们的研究表明，血清素通过 5-HT1A 和 5-HT2A/C 受体激活，以相反的方式调节 PFC 神经元中的 NMDAR 功能。 5-HT2A/C 通过 β-arrestin 依赖性途径激活 ERK，对抗 5-HT1A 对微管稳定性和 NMDAR 转运的破坏。这些发现为理解 PFC 中血清素和 NMDAR 之间复杂的相互作用提供了一个框架，这对于两个系统都高度参与的认知和情绪控制非常重要。
Abnormal serotonin-glutamate interaction in prefrontal cortex (PFC) is implicated in the pathophysiology of many mental disorders, including schizophrenia and depression. However, the mechanisms by which this interaction occurs remain unclear. Our previous study has shown that activation of 5-HT1A receptors inhibits N-methyl-d-aspartate (NMDA) receptor (NMDAR) currents in PFC pyramidal neurons by disrupting microtubule-based transport of NMDARs. Here we found that activation of 5-HT2A/C receptors significantly attenuated the effect of 5-HT1A on NMDAR currents and microtubule depolymerization. The counteractive effect of 5-HT2A/C on 5-HT1A regulation of synaptic NMDAR response was also observed in PFC pyramidal neurons from intact animals treated with various 5-HT-related drugs. Moreover, 5-HT2A/C stimulation triggered the activation of extracellular signal-regulated kinase (ERK) in dendritic processes. Inhibition of the β-arrestin/Src/dynamin signaling blocked 5-HT2A/C activation of ERK and the counteractive effect of 5-HT2A/C on 5-HT1A regulation of NMDAR currents. Immunocytochemical studies showed that 5-HT2A/C treatment blocked the inhibitory effect of 5-HT1A on surface NR2B clusters on dendrites, which was prevented by cellular knockdown of β-arrestins. Taken together, our study suggests that serotonin, via 5-HT1A and 5-HT2A/C receptor activation, regulates NMDAR functions in PFC neurons in a counteractive manner. 5-HT2A/C, by activating ERK via the β-arrestin-dependent pathway, opposes the 5-HT1A disruption of microtubule stability and NMDAR transport. These findings provide a framework for understanding the complex interactions between serotonin and NMDARs in PFC, which could be important for cognitive and emotional control in which both systems are highly involved.