Molecular mechanism of strengthening synaptic connection by neural activity.

我们研究了活性调节的黏附分子arcadlin的作用。Arcadlin在神经元中合成，并被运送到突触，可能参与突触活动刺激的突触重组。在这里，我们分析了TAO2与Arcadlin细胞质区域的相互作用。Arcadlin胞外(EC)结构域的同亲结合激活了TAO2及其下游的MKK3和p38MAPK。这种亲和性的相互作用也诱导了牛至碱本身的内化。这种内化完全被显性-负性Dynamin的共表达所阻断，表明arcadlin是通过网状蛋白介导的内吞作用内化的。MKK3和p38Mark的缺失导致了arcadlin内吞作用的丧失。此外，p38Mark抑制剂SB203580也能抑制arcadlin的内吞作用。这些结果表明，TAO2受arcadlin EC结构域亲和性结合的刺激，激活p38MAPK途径，诱导arcadlin内吞。因此，神经活动可能通过调节突触膜表面细胞黏附分子的数量来改变突触连接的强度。

We investigated the role of activity-regulated adhesion molecule arcadlin. Arcadlin is synthesized in neurons and carried to synapses and may be involved in synaptic reorganization stimulated by synaptic activity. Here, we analyzed the interaction of TAO2 with the cytoplasmic region of Arcadlin. Homophilic binding of extracellular (EC) domains of arcadlin activated TAO2 and its down-stream kinases, MKK3 and p38 MAP kinase. The homophilic interaction also induced the internalization of arcadlin itself. This internalization was completely blocked by the co-expression of dominant-negative dynamin, indicating that arcadlin was internalized by clathrin-mediated endocytosis. The absence of MKK3 and p38 MARK resulted in a loss of arcadlin endocytosis. Moreover, p38 MARK inhibitor SB203580 also inhibited the endocytosis of arcadlin. These results suggest that TAO2, stimulated by homophilic binding of arcadlin EC domains, activates p38 MAP kinase pathway and induces the endocytosis of arcadlin. Thus, neural activity may play a role in changing the strength of synaptic connections by regulating the number of cell adhesion molecules on the surface of synaptic membranes.