Functional analyses of a novel neural adhesion molecule regulated by synaptic activity

突触活性调节的新型神经粘附分子的功能分析

• 批准号: 11680772
• 负责人: YAMAGATA Kanato
• 金额: $ 2.37万
• 依托单位: Tokyo Metropolitan Institute for Neuroscience
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11680772/
• 关键词: Neural activity; cell adhesion molecule; arcadlin; MAPキナーゼ; シナプス; 神経可塑性

To examine the molecular basis of activity-dependent plasticity, we have used differential cloning techniques to identify genes that are repidly induced in brain neurons by synaptic activity. Here, we identify a novel cadherin molecule Arcadlin (activity-regulated cadherin-like protein). arcadlin mRNA is rapidly and transiently induced in hippocampal granule cells by seizures and by NMDA-dependent synaptic activity in LTP.The extracellular domain of Arcadlin is most homologous to protocadherin-8 ; however, the cytoplasmic region is distinct from that of any cadherin family member. Arcadlin protein is expressed at the synapses and shows a homophilic binding activity in a Ca^<2+>-dependent manner. Application of Arcadlin antibody reduces EPSP amplitude and blocks LTP in hippocampal slices. Two-hybrid screening identified the cytoplasmic region bound to TAO2 kinase. Furthermore, homophilic binding of extracellular domains activated the cytoplasmic region of Arcadlin, TAO2, MKK3 and p38 MAP kinase sequentially. Its close homology with cadherins, its rapid inducibility by neural activity, its involvement in synaptic transmission and its activation of p38 MAP kinase pathway suggest that Arcadlin may play an important role in activity-induced synaptic reorganization underlying long term memory.

为了研究活动依赖性可塑性的分子基础，我们使用了差异克隆技术来鉴定在脑神经元中由突触活动快速诱导的基因。在这里，我们确定了一种新的钙粘蛋白分子Arcadlin（活性调节钙粘蛋白样蛋白）。Arcadlin mRNA在海马颗粒细胞中被癫痫发作和LTP中的NMDA依赖性突触活动快速和短暂地诱导。Arcadlin的胞外区与原钙粘蛋白-8同源性最高;然而，胞浆区与任何钙粘蛋白家族成员的胞浆区不同。Arcadlin蛋白在突触处表达，并以Ca^<2+>依赖性方式显示出嗜同性结合活性。Arcadlin抗体的应用降低了海马脑片的EPSP振幅并阻断了LTP。双杂交筛选鉴定了与TAO 2激酶结合的胞质区域。此外，细胞外结构域的嗜同性结合依次激活了Arcadlin、TAO 2、MKK 3和p38 MAP激酶的胞浆区。Arcadlin与钙粘蛋白同源性高，可被神经活动快速诱导，参与突触传递，激活p38 MAP激酶通路，提示Arcadlin可能在活动诱导的长时程记忆突触重组中起重要作用。

项目成果

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Irie Y 等人：“amida 的分子克隆和表征，这是一种与神经元特异性立即早期基因产物弧相互作用的新型蛋白质，包含新型核定位信号，并导致培养细胞中的细胞死亡。”J Biol Chem。

Yamagata K et al.: "Induction of arc, and effector immediate early gene, by methamphetamine."Ann N Y Acad Sci. 914. 22-32 (2000)

Yamagata K 等人：“通过甲基苯丙胺诱导电弧和效应器立即早期基因。”Ann N Y Acad Sci。