The dynamic trafficking of AMPA receptors (AMPARs), which enables the endocytosis, recycling, and exocytosis of AMPARs, is crucial for synaptic plasticity. Endophilin2, which directly interacts with the GluA1 subunit of AMPARs, plays an important role in AMPAR endocytosis. Collapsin response mediator protein 2 (CRMP2) promotes the maturation of the dendritic spine and can transfer AMPARs to the membrane. Although the mechanisms of AMPAR endocytosis and exocytosis are well known, the exact molecular mechanisms underlying AMPAR recycling remain unclear. Here, we report a unique interaction between CRMP2 and endophilin2. Our results showed that overexpression of CRMP2 and endophilin2 increased the amplitude and frequency of miniature excitatory synaptic currents (mEPSCs) and modestly enhanced AMPAR levels in hippocampal neurons. Furthermore, the CRMP2 and endophilin2 overexpression phenotype failed to occur when the interaction between these two proteins was inhibited. Further analysis revealed that this interaction was regulated by CRMP2 phosphorylation. The phosphorylation of CRMP2 inhibited its interaction with endophilin2; this was mainly affected by the phosphorylation of Thr514 and Ser518 by glycogen synthase kinase (GSK) 3β. CRMP2 phosphorylation increased degradation and inhibited the surface expression of AMPAR GluA1 subunits in cultured hippocampal neurons. However, the dephosphorylation of CRMP2 inhibited degradation and promoted the surface expression of AMPAR GluA1 subunits in cultured hippocampal neurons. Taken together, our data demonstrated that the interaction between CRMP2 and endophilin2 was conductive to the recycling of AMPA receptor GluA1 subunits in hippocampal neurons.

AMPA受体（AMPAR）的动态运输能够使AMPAR发生内吞，再循环和胞吐作用，这对于突触可塑性至关重要。与AMPAR的GluA1亚单位直接相互作用的Endophilin2在AMPAR的内吞作用中起着重要的作用。胶原蛋白反应介质蛋白2（CRMP2）促进树突棘的成熟，并且可以将AMPARs转移到膜上。尽管AMPAR内吞作用和胞吐作用的机制是众所周知的，但AMPAR循环背后的确切分子机制仍不清楚。在这里，我们报告CRMP2和endophilin2之间的独特相互作用。我们的研究结果表明，CRMP2和Endophilin2的过表达增加了微型兴奋性突触电流（mEPSC）的幅度和频率，并适度增强了海马神经元的AMPAR水平。此外，当这两个蛋白之间的相互作用被抑制时，CRMP2和endophilin2的过量表达表型就不会发生。进一步的分析表明，这种相互作用受CRMP2磷酸化的调节。CRMP2的磷酸化抑制了它与endophilin2的相互作用。这主要受糖原合酶激酶（GSK）3β对Thr514和Ser518磷酸化的影响。CRMP2磷酸化增加了降解，并抑制了培养的海马神经元中AMPAR GluA1亚基的表面表达。然而，CRMP2的去磷酸化抑制了降解并促进了培养的海马神经元中AMPAR GluA1亚基的表面表达。在一起