The synaptic balance between sumoylation and desumoylation is maintained by the activation of metabotropic mGlu5 receptors

Cell Mol Life Sci. 2019 Aug;76(15):3019-3031. doi: 10.1007/s00018-019-03075-8. Epub 2019 Mar 23.


Sumoylation is a reversible post-translational modification essential to the modulation of neuronal function, including neurotransmitter release and synaptic plasticity. A tightly regulated equilibrium between the sumoylation and desumoylation processes is critical to the brain function and its disruption has been associated with several neurological disorders. This sumoylation/desumoylation balance is governed by the activity of the sole SUMO-conjugating enzyme Ubc9 and a group of desumoylases called SENPs, respectively. We previously demonstrated that the activation of type 5 metabotropic glutamate receptors (mGlu5R) triggers the transient trapping of Ubc9 in dendritic spines, leading to a rapid increase in the overall synaptic sumoylation. However, the mechanisms balancing this increased synaptic sumoylation are still not known. Here, we examined the diffusion properties of the SENP1 enzyme using a combination of advanced biochemical approaches and restricted photobleaching/photoconversion of individual hippocampal spines. We demonstrated that the activation of mGlu5R leads to a time-dependent decrease in the exit rate of SENP1 from dendritic spines. The resulting post-synaptic accumulation of SENP1 restores synaptic sumoylation to initial levels. Altogether, our findings reveal the mGlu5R system as a central activity-dependent mechanism to maintaining the homeostasis of sumoylation at the mammalian synapse.

Keywords: Desumoylation; SENP1; Sumoylation; Synapse; mGlu5 receptor.

MeSH terms

  • Animals
  • COS Cells
  • Cells, Cultured
  • Chlorocebus aethiops
  • Cysteine Endopeptidases / metabolism
  • Fluorescence Recovery After Photobleaching
  • Humans
  • Microscopy, Fluorescence
  • Neurons / cytology
  • Neurons / metabolism
  • Rats, Wistar
  • Receptor, Metabotropic Glutamate 5 / metabolism*
  • SUMO-1 Protein / metabolism
  • Sumoylation
  • Synapses / metabolism*
  • Ubiquitin-Conjugating Enzymes / metabolism


  • GRM5 protein, human
  • Receptor, Metabotropic Glutamate 5
  • SUMO-1 Protein
  • Ubiquitin-Conjugating Enzymes
  • Cysteine Endopeptidases
  • SENP1 protein, rat
  • ubiquitin-conjugating enzyme UBC9