Transducing Neuronal Activity into Dendritic Spine Morphology: New Roles for p38 MAP Kinase and N-cadherin
Transducing Neuronal Activity into Dendritic Spine Morphology: New Roles for p38 MAP Kinase and N-cadherin
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DOI：
10.1177/1073858408324024
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发表时间：
2009-02
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影响因子：
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通讯作者：
H. Sugiura;Hidekazu Tanaka;Shin Yasuda;T. Takemiya;K. Yamagata
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作者：
H. Sugiura;Hidekazu Tanaka;Shin Yasuda;T. Takemiya;K. Yamagata
突触可塑性依赖于突触的产生、修饰和断开。兴奋性突触连接到称为棘的专门树突隔室，其经历活动诱导的重塑。在这里，我们讨论了一个信号转导通路，通过p38丝裂原活化蛋白激酶（MAPK）和N-钙粘蛋白的神经元活动到脊柱的重塑。树突棘改变其形态和密度响应神经元的活动。在早期阶段，突触分子的翻译后修饰调节棘形态，而活动诱导的基因产物在晚期阶段降低棘密度。这些机制的靶点之一是N-钙粘蛋白。一种活性诱导的原钙粘蛋白（rocadlin）可刺激一千零一个2β（TAO 2 β）激酶，进而通过MAPK激酶3（MEK 3）激活p38 MAPK，导致N-钙粘蛋白的内吞作用和棘数目的减少。这一途径也是神经元疾病（如阿尔茨海默病和癫痫）中脊柱减少的机制的基础。新的p38 MAPK抑制剂的开发为这些患者开发更有效的疗法带来了一线希望。
Synaptic plasticity depends on the generation, modification and disconnection of synapses. An excitatory synapse is connected to a specialized dendritic compartment called a spine, which undergoes activity-induced remodeling. Here, we discuss a signaling pathway that transduces neuronal activity into the remodeling of spine through p38 mitogen-activated protein kinase (MAPK) and N-cadherin. Dendritic spines change their morphology and density in response to neuronal activity. In the early phase, posttranslational modifications of synaptic molecules regulate spine morphology, whereas activity-induced gene products reduce spine density in the late phase. One of the targets of these mechanisms is N-cadherin. An activity-induced protocadherin, arcadlin, stimulates thousand and one 2β (TAO2β) kinase, which in turn activates p38 MAPK through MAPK kinase 3 (MEK3), resulting in the endocytosis of N-cadherin and the decrease in spine number. This pathway also underlies the mechanism of the spine decrease in neuronal disorders, such as Alzheimer's disease and epilepsy. Development of new p38 MAPK inhibitors brings a ray of hope with respect to the development of more effective therapies for these patients.