Pin1-dependent signalling negatively affects GABAergic transmission by modulating neuroligin2/gephyrin interaction

Nat Commun. 2014 Oct 9;5:5066. doi: 10.1038/ncomms6066.

Abstract

The cell adhesion molecule Neuroligin2 (NL2) is localized selectively at GABAergic synapses, where it interacts with the scaffolding protein gephyrin in the post-synaptic density. However, the role of this interaction for formation and plasticity of GABAergic synapses is unclear. Here, we demonstrate that endogenous NL2 undergoes proline-directed phosphorylation at its unique S714-P consensus site, leading to the recruitment of the peptidyl-prolyl cis-trans isomerase Pin1. This signalling cascade negatively regulates NL2's ability to interact with gephyrin at GABAergic post-synaptic sites. As a consequence, enhanced accumulation of NL2, gephyrin and GABAA receptors was detected at GABAergic synapses in the hippocampus of Pin1-knockout mice (Pin1-/-) associated with an increase in amplitude of spontaneous GABAA-mediated post-synaptic currents. Our results suggest that Pin1-dependent signalling represents a mechanism to modulate GABAergic transmission by regulating NL2/gephyrin interaction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / metabolism*
  • Cell Adhesion Molecules, Neuronal / metabolism*
  • GABAergic Neurons / metabolism*
  • Hippocampus / metabolism*
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Nerve Tissue Proteins / metabolism*
  • Peptidylprolyl Isomerase / genetics*
  • Peptidylprolyl Isomerase / metabolism
  • Phosphorylation
  • Post-Synaptic Density / metabolism*
  • Receptors, GABA-A / metabolism*
  • Signal Transduction
  • Synapses / metabolism
  • Synaptic Transmission / physiology*
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Carrier Proteins
  • Cell Adhesion Molecules, Neuronal
  • Membrane Proteins
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Nerve Tissue Proteins
  • Receptors, GABA-A
  • gephyrin
  • neuroligin 2
  • gamma-Aminobutyric Acid
  • Peptidylprolyl Isomerase
  • Pin1 protein, mouse