Several posttranslational modifications act in concert to regulate gephyrin scaffolding and GABAergic transmission

Nat Commun. 2016 Nov 7:7:13365. doi: 10.1038/ncomms13365.


GABAA receptors (GABAARs) mediate the majority of fast inhibitory neurotransmission in the brain via synergistic association with the postsynaptic scaffolding protein gephyrin and its interaction partners. However, unlike their counterparts at glutamatergic synapses, gephyrin and its binding partners lack canonical protein interaction motifs; hence, the molecular basis for gephyrin scaffolding has remained unclear. In this study, we identify and characterize two new posttranslational modifications of gephyrin, SUMOylation and acetylation. We demonstrate that crosstalk between SUMOylation, acetylation and phosphorylation pathways regulates gephyrin scaffolding. Pharmacological intervention of SUMO pathway or transgenic expression of SUMOylation-deficient gephyrin variants rescued gephyrin clustering in CA1 or neocortical neurons of Gabra2-null mice, which otherwise lack gephyrin clusters, indicating that gephyrin SUMO modification is an essential determinant for scaffolding at GABAergic synapses. Together, our results demonstrate that concerted modifications on a protein scaffold by evolutionarily conserved yet functionally diverse signalling pathways facilitate GABAergic transmission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Animals
  • CA1 Region, Hippocampal / cytology
  • CA1 Region, Hippocampal / physiology
  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology*
  • Female
  • Flavones / pharmacology
  • GABAergic Neurons / physiology*
  • HEK293 Cells
  • Humans
  • Male
  • Membrane Proteins / metabolism
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Animal
  • Neocortex / cytology
  • Neocortex / metabolism
  • Phosphorylation
  • Primary Cell Culture
  • Rats
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Sumoylation / drug effects
  • Synapses / physiology
  • Synaptic Transmission / physiology*


  • 2',3',4'-trihydroxyflavone
  • Carrier Proteins
  • Flavones
  • Gabra2 protein, mouse
  • Membrane Proteins
  • Receptors, GABA-A
  • gephyrin