PRRT2 Mutant Leads to Dysfunction of Glutamate Signaling

Int J Mol Sci. 2015 Apr 23;16(5):9134-51. doi: 10.3390/ijms16059134.


Paroxysmal kinesigenic choreoathetosis (PKC) is an inherited disease of the nervous system. We previously identified PRRT2 as the causative gene of PKC. However, as little is known about the function of PRRT2, elucidating its function will benefit not only PKC studies, but also many other related disorders. Here, we reveal higher levels of glutamate in the plasma of PKC patients and the culture medium of neurons following knock-out Prrt2 expression. Using double immunostaining assays we confirm Prrt2 is located at the glutamatergic neurons in accordance with its function. Our co-immunoprecipitation assays reveal mutant PRRT2 interferes with SNAP25 and GRIA1 interactions, respectively. Furthermore, using live-labeling techniques, we confirmed co-transfection with mutant PRRT2 caused an increase in GRIA1 distribution on the cell surface. Therefore, our results suggest that mutant PRRT2, probably through its weakened interaction with SNAP25, affects glutamate signaling and glutamate receptor activity, resulting in the increase of glutamate release and subsequent neuronal hyperexcitability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Animals
  • Aspartic Acid / metabolism
  • Case-Control Studies
  • Cell Line
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Child
  • Dystonia / genetics
  • Dystonia / metabolism
  • Female
  • Gene Knockout Techniques
  • Glutamates / metabolism*
  • Glycine / metabolism
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Mutation*
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism
  • Protein Binding
  • Receptors, AMPA / metabolism
  • Signal Transduction*
  • Young Adult


  • Glutamates
  • Membrane Proteins
  • Nerve Tissue Proteins
  • PRRT2 protein, human
  • Receptors, AMPA
  • Aspartic Acid
  • Glycine
  • glutamate receptor ionotropic, AMPA 1

Supplementary concepts

  • Familial paroxysmal dystonia