GRIP1 Binds to ApoER2 and EphrinB2 to Induce Activity-Dependent AMPA Receptor Insertion at the Synapse

Cell Rep. 2017 Oct 3;21(1):84-96. doi: 10.1016/j.celrep.2017.09.019.


Regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking in response to neuronal activity is critical for synaptic function and plasticity. Here, we show that neuronal activity induces the binding of ephrinB2 and ApoER2 receptors at the postsynapse to regulate de novo insertion of AMPA receptors. Mechanistically, the multi-PDZ adaptor glutamate-receptor-interacting protein 1 (GRIP1) binds ApoER2 and bridges a complex including ApoER2, ephrinB2, and AMPA receptors. Phosphorylation of ephrinB2 in a serine residue (Ser-9) is essential for the stability of such a complex. In vivo, a mutation on ephrinB2 Ser-9 in mice results in a complete disruption of the complex, absence of ApoER2 downstream signaling, and impaired activity-induced and ApoER2-mediated AMPA receptor insertion. Using compound genetics, we show the requirement of this complex for long-term potentiation (LTP). Together, our findings uncover a cooperative ephrinB2 and ApoER2 signaling at the synapse, which serves to modulate activity-dependent AMPA receptor dynamic changes during synaptic plasticity.

Keywords: AMPA receptors; ApoER2; GRIP1; LTP; ephrinB; synaptic plasticity.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Ephrin-B2 / genetics*
  • Ephrin-B2 / metabolism
  • Gene Expression Regulation
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • LDL-Receptor Related Proteins / genetics*
  • LDL-Receptor Related Proteins / metabolism
  • Long-Term Potentiation / physiology*
  • Mice
  • Mice, Transgenic
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurons / cytology
  • Neurons / metabolism
  • Phosphorylation
  • Primary Cell Culture
  • Protein Binding
  • Protein Transport
  • Receptors, AMPA / genetics*
  • Receptors, AMPA / metabolism
  • Serine / metabolism
  • Signal Transduction
  • Synapses / metabolism*


  • Adaptor Proteins, Signal Transducing
  • EFNB2 protein, mouse
  • Ephrin-B2
  • Grip1 protein, mouse
  • LDL-Receptor Related Proteins
  • Nerve Tissue Proteins
  • Receptors, AMPA
  • low density lipoprotein receptor-related protein 8
  • Serine