Megeath L J, Kirber M T, Hopf C, Hoch W, Fallon J R
Department of Neuroscience, Brown University, Box 1953, 190 Thayer Street, Providence, RI 02912, USA.
Neuroscience. 2003;122(3):659-68. doi: 10.1016/s0306-4522(03)00602-x.
Although much progress has been made in understanding synapse formation, little is known about the mechanisms underlying synaptic maintenance and loss. The formation of agrin-induced AChR clusters on cultured myotubes requires both activation of the receptor tyrosine kinase MuSK and intracellular calcium fluxes. Here, we provide evidence that such AChR clusters are maintained by agrin/MuSK-induced intracellular calcium fluxes. Clamping intracellular calcium fluxes after AChR clusters have formed leads to rapid MuSK and AChR tyrosine dephosphorylation and cluster dispersal, even in the continued presence of agrin. Both the dephosphorylation and the dispersal are inhibited by the tyrosine phosphatase inhibitor pervanadate. In contrast, clamping intracellular calcium at the time of initial agrin stimulation has no effect on agrin-induced MuSK or AChR phosphorylation, but blocks AChR cluster formation. These findings suggest an avenue by which postsynaptic stability can be regulated by modification of intracellular signaling pathways that are distinct from those used during synapse formation.
尽管在理解突触形成方面已经取得了很大进展，但对于突触维持和丧失的潜在机制却知之甚少。在培养的肌管上形成聚集蛋白诱导的乙酰胆碱受体（AChR）簇既需要受体酪氨酸激酶MuSK的激活，也需要细胞内钙通量。在这里，我们提供证据表明，此类AChR簇由聚集蛋白/MuSK诱导的细胞内钙通量维持。在AChR簇形成后钳制细胞内钙通量会导致MuSK和AChR酪氨酸快速去磷酸化以及簇的分散，即使在聚集蛋白持续存在的情况下也是如此。酪氨酸磷酸酶抑制剂过氧钒酸盐可抑制去磷酸化和分散。相反，在最初的聚集蛋白刺激时钳制细胞内钙对聚集蛋白诱导的MuSK或AChR磷酸化没有影响，但会阻止AChR簇的形成。这些发现提示了一条途径，通过该途径可以通过修饰与突触形成过程中所使用的信号通路不同的细胞内信号通路来调节突触后稳定性。
