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

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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.