Anchoring and synaptic stability of PSD-95 is driven by ephrin-B3

Nat Neurosci. 2015 Nov;18(11):1594-605. doi: 10.1038/nn.4140. Epub 2015 Oct 19.


Organization of signaling complexes at excitatory synapses by membrane-associated guanylate kinase (MAGUK) proteins regulates synapse development, plasticity, senescence and disease. Post-translational modification of MAGUK family proteins can drive their membrane localization, yet it is unclear how these intracellular proteins are targeted to sites of synaptic contact. Here we show using super-resolution imaging, biochemical approaches and in vivo models that the trans-synaptic organizing protein ephrin-B3 controls the synaptic localization and stability of PSD-95 and links these events to changes in neuronal activity via negative regulation of a newly identified mitogen-associated protein kinase (MAPK)-dependent phosphorylation site on ephrin-B3, Ser332. Unphosphorylated ephrin-B3 was enriched at synapses, and interacted directly with and stabilized PSD-95 at synapses. Activity-induced phosphorylation of Ser332 dispersed ephrin-B3 from synapses, prevented the interaction with PSD-95 and enhanced the turnover of PSD-95. Thus, ephrin-B3 specifies the synaptic localization of PSD-95 and likely links the synaptic stability of PSD-95 to changes in neuronal activity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cats
  • Disks Large Homolog 4 Protein
  • Ephrin-B3 / genetics
  • Ephrin-B3 / metabolism*
  • Female
  • Guanylate Kinases / genetics
  • Guanylate Kinases / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Neurons / metabolism*
  • Pregnancy
  • Protein Processing, Post-Translational / genetics
  • Rats
  • Receptors, AMPA / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / metabolism*


  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Ephrin-B3
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Mpp2 protein, rat
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Guanylate Kinases