Encoding and transducing the synaptic or extrasynaptic origin of NMDA receptor signals to the nucleus

Cell. 2013 Feb 28;152(5):1119-33. doi: 10.1016/j.cell.2013.02.002.


The activation of N-methyl-D-aspartate-receptors (NMDARs) in synapses provides plasticity and cell survival signals, whereas NMDARs residing in the neuronal membrane outside synapses trigger neurodegeneration. At present, it is unclear how these opposing signals are transduced to and discriminated by the nucleus. In this study, we demonstrate that Jacob is a protein messenger that encodes the origin of synaptic versus extrasynaptic NMDAR signals and delivers them to the nucleus. Exclusively synaptic, but not extrasynaptic, NMDAR activation induces phosphorylation of Jacob at serine-180 by ERK1/2. Long-distance trafficking of Jacob from synaptic, but not extrasynaptic, sites depends on ERK activity, and association with fragments of the intermediate filament α-internexin hinders dephosphorylation of the Jacob/ERK complex during nuclear transit. In the nucleus, the phosphorylation state of Jacob determines whether it induces cell death or promotes cell survival and enhances synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Nucleus / metabolism*
  • Cell Survival
  • Cells, Cultured
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Gene Expression Regulation
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Intermediate Filament Proteins / metabolism
  • Long-Term Potentiation
  • Long-Term Synaptic Depression
  • MAP Kinase Signaling System
  • Mice
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphorylation
  • Rats
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Synapses / metabolism*


  • Cyclic AMP Response Element-Binding Protein
  • Intermediate Filament Proteins
  • Jacob protein, mouse
  • Nerve Tissue Proteins
  • Nsmf protein, rat
  • Receptors, N-Methyl-D-Aspartate
  • alpha-internexin
  • Phosphoric Monoester Hydrolases