Phosphorylation of CRMP2 by Cdk5 Negatively Regulates the Surface Delivery and Synaptic Function of AMPA Receptors

AMPA receptor mediate most fast excitatory synaptic transmission and play a key role in synaptic plasticity in the central nervous system (CNS) by trafficking and targeting of its subunits to individual postsynaptic membrane. Collapsing response mediator protein 2 (CRMP2), an intracellular phospho-protein, has been reported to promote the maturation of the dendritic spine and transfer AMPA receptors to the membrane. However, our knowledge about the molecular mechanisms of CRMP2 regulating AMPA receptors trafficking is limited. Here, we reported that CRMP2 promoted the surface expression of AMPA receptor GluA1 subunit in cultured hippocampal neurons and in HEK293T cells expressing GluA1 subunits. Furthermore, we found that CRMP2 interacted with GluA1, and their interaction was inhibited by CRMP2 phosphorylation at ser522. Moreover, our results showed that phosphorylation of CRMP2 at ser522 by cyclin-dependent kinase 5 (Cdk5) decreased the fluorescence intensity of surface GluA1 and the amplitude and frequency of miniature excitatory synaptic currents (mEPSCs) in cultured hippocampal neurons, indicating a reduction levels and synaptic function of AMPA receptors. Taken together, our data demonstrated that phosphorylation of CRMP2 by Cdk5 is important for AMPA receptor surface delivery in hippocampal neurons.