Erk/MAPK信号通路对基底神经节运动控制作用的差异调控

The Erk/MAPK Signaling Pathway on Motor Behavior Control of Basal Ganglia

细胞外信号调节激酶1和2(Erk1/2)是一种丝氨酸/苏氨酸蛋白激酶,属于丝裂原活化蛋白激酶(MAPK)家族的关键成员,通过磷酸化细胞质和细胞核内的多种底物参与正常及病理状态下的细胞活动。以纹状体为核心的基底神经节(basal ganglia,BG)被认为是运动控制相关的重要结构。Erk1/2通过对纹状体胞外多巴胺(DA)和谷氨酸(Glu)信号进行整合,协调了细胞增殖、分化及转录和翻译等重要细胞事件。研究显示,纹状体多巴胺受体1型中等多棘神经元(D1-MSNs)和多巴胺受体2型中等多棘神经元(D2-MSNs)上,Erk/MAPK信号通路具有差异性调控运动行为的作用。纹状体D1-MSNs的Erk1/2通过多巴胺D1样受体(D1R)激活cAMP/PKA通路促进运动行为,D2-MSNs的Erk1/2通过多巴胺D2样受体(D2R)和α-氨-3-羟基-5-甲基-4-异恶唑丙酸受体(AMPAR)抑制运动行为。此外,Erk/MAPK信号通路还能参与调节帕金森病(PD)、亨廷顿病及成瘾行为相关的病理生理学进程。Erk/MAPK信号通路干预能够有效缓解相关运动功能障碍。因此,本文围绕Erk/MAPK信号通路对基底神经节运动行为调控的影响,以及该信号通路在PD等神经系统相关运动功能障碍发生中的分子生物学机制进行总结,为相关疾病的治疗及预防提供新的视角。

Extracellular signal regulated kinase 1/2(Erk1/2)is a serine/threonine protein kinase,which belongs to the key member of the mitogen activated protein kinase(MAPK)family.It participates in cell activities under normal and pathological conditions by phosphorylating a variety of substrates in the cytoplasm and nucleus.The basal ganglia(BG)with the striatum as the core is considered to be a significant structure for the regulation of motor behavior.The Erk/MAPK cascade is the most important signal transduction pathway in the MAPK signaling pathway.It is also closely related to the regulation of voluntary movements in basal ganglia.Erk1/2 coordinates essential cellular events such as cell proliferation,growth,differentiation,transcription and translation activities by responding to extracellular dopamine(DA)and glutamate(Glu)signals,to engage in the regulation of motor behaviors.It was found that the Erk/MAPK signaling pathway on D1-dopamine receptor-expressing medium spiny neurons(D1-MSNs)and D2-dopamine receptor-expressing medium spiny neurons(D2-MSNs)in the striatum has the effect of differential regulation of motor behaviors.Erk1/2 on D1 MSNs in striatum activates the cAMP/PKA pathway through the D1-dopamine receptor(D1R)to promote motor behaviors,and Erk1/2 on D2-MSNs through the D2-dopamine receptor(D2R)and theα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor(AMPAR)inhibits behavior.In addition,the Erk/MAPK signaling pathway can also regulate pathophysiological processes related to Parkinson’s disease(PD),Huntington’s disease and addictive behaviors.Erk/MAPK signaling pathway intervention can effectively alleviate related motor dysfunctions.Therefore,this paper summarizes the effect of the Erk/MAPK signal pathway on the regulation of BG motor behaviors and the molecular biological mechanism of this signal pathway in the occurrence of nervous system related motor dysfunctions such as PD.It provides a new perspective on the treatment and prevention of related diseases.