Cell Rep. 2017 Oct 3;21(1):84-96. doi: 10.1016/j.celrep.2017.09.019.
GRIP1 Binds to ApoER2 and EphrinB2 to Induce Activity-Dependent AMPA Receptor Insertion at the Synapse.
Neuronal activity at the synapse induces changes in synaptic strength by altering the abundance of receptors at the membrane. Thus, changes in AMPA receptor abundance are thought to underlie the regulation of synaptic strength during synaptic plasticity and homeostatic scaling. During long-term potentiation (LTP), AMPA receptors are incorporated into the postsynaptic membrane, thereby increasing postsynaptic potentials. Elucidating the machinery regulating the new insertion of AMPA receptors at the synapse is therefore essential to understand the basic molecular events underlying synaptic transmission, learning, and memory. In this work, the authors clarified that neuronal activity not only induces the clustering of the apolipoprotein E receptor 2 (ApoER2) and the transmembrane ligand for ephrin receptors ephrinB2 at postsynaptic sites but also initiates downstream signaling, resulting in the phosphorylation of the intracellular adaptor protein Dab1. They demonstrated that ephrinB2 is required for the activity-induced and ApoER2-mediated de novo insertion of AMPA receptors in the postsynaptic membrane, a process that specifically relies on the serine residue Ser-9 in the cytoplasmic tail of ephrinB2. Mechanistically, it was shown that GRIP1 molecules (a multiple-PDZ-domain-containing adaptor molecule that also binds to the GluR2 subunit of AMPA receptors) bridge a complex consisting of ephrinB2/ApoER2/GluR2. Using compound genetics, the authors showed the requirement for such a complex for the function of ApoER2 in regulating AMPA receptor insertion and LTP. Together, the findings uncover a cooperative ephrinB2 and ApoER2 signaling at the synapse, which together with GRIP1 serves to modulate activity-dependent AMPA receptor dynamic changes during synaptic plasticity.