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

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由突触活动在脑神经元中快速诱导的基因。在这里，我们鉴定了一种新的钙粘蛋白分子Arcadlin（活性调节钙粘蛋白样蛋白）。癫痫发作和LTP中nmda依赖的突触活动可迅速、短暂地诱导海马颗粒细胞中的arcadlin mRNA。Arcadlin的胞外结构域与原钙粘蛋白-8最同源；然而，细胞质区域不同于任何钙粘蛋白家族成员。Arcadlin蛋白在突触上表达，并以Ca^<2+>依赖的方式显示出亲同型结合活性。应用Arcadlin抗体可降低EPSP振幅，阻断海马切片的LTP。双杂交筛选鉴定了与TAO2激酶结合的细胞质区域。此外，胞外结构域的亲同结合依次激活了Arcadlin、TAO2、MKK3和p38 MAP激酶的细胞质区域。其与钙粘蛋白的密切同源性、可被神经活动快速诱导、参与突触传递和激活p38 MAP激酶途径表明，Arcadlin可能在长期记忆活动诱导的突触重组中发挥重要作用。

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.