Post-phosphorylation prolyl isomerisation of gephyrin represents a mechanism to modulate glycine receptors function

EMBO J. 2007 Apr 4;26(7):1761-71. doi: 10.1038/sj.emboj.7601625. Epub 2007 Mar 8.


The microtubule binding protein gephyrin plays a prominent role in establishing and maintaining a high concentration of inhibitory glycine receptors juxtaposed to presynaptic releasing sites. Here, we show that endogenous gephyrin undergoes proline-directed phosphorylation, which is followed by the recruitment of the peptidyl-prolyl isomerase Pin1. The interaction between gephyrin and Pin1 is strictly dependent on gephyrin phosphorylation and requires serine-proline consensus sites encompassing the gephyrin proline-rich domain. Upon binding, Pin1 triggers conformational changes in the gephyrin molecule, thus enhancing its ability to bind the beta subunit of GlyRs. Consistently, a downregulation of GlyR clusters was detected in hippocampal neurons derived from Pin1 knockout mice, which was paralleled by a reduction in the amplitude of glycine-evoked currents. Our results suggest that phosphorylation-dependent prolyl isomerisation of gephyrin represents a mechanism for regulating GlyRs function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Cytoplasmic Structures / metabolism
  • Epitopes
  • Evoked Potentials
  • Hippocampus / cytology
  • Hippocampus / enzymology
  • Humans
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Neurons / cytology
  • Neurons / enzymology
  • Peptidylprolyl Isomerase / deficiency
  • Peptidylprolyl Isomerase / metabolism*
  • Phosphorylation
  • Proline / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Subunits / metabolism
  • Receptors, Glycine / metabolism*
  • Recombinant Proteins / metabolism
  • Serine / metabolism


  • Carrier Proteins
  • Epitopes
  • Membrane Proteins
  • NIMA-Interacting Peptidylprolyl Isomerase
  • Protein Subunits
  • Receptors, Glycine
  • Recombinant Proteins
  • gephyrin
  • Serine
  • Proline
  • PIN1 protein, human
  • Peptidylprolyl Isomerase
  • Pin1 protein, mouse