Activity-dependent cleavage of dyskinesia-related proline-rich transmembrane protein 2 (PRRT2) by calpain in mouse primary cortical neurons

FASEB J. 2020 Jan;34(1):180-191. doi: 10.1096/fj.201902148R. Epub 2019 Nov 20.

Abstract

Mutations of PRRT2 (proline-rich transmembrane protein 2) cause several neurological disorders, represented by paroxysmal kinesigenic dyskinesia (PKD), which is characterized by attacks of involuntary movements triggered by sudden voluntary movements. PRRT2 is reported to suppress neuronal excitation, but it is unclear how the function of PRRT2 is modulated during neuronal excitation. We found that PRRT2 is processed to a 12 kDa carboxy-terminal fragment (12K-CTF) by calpain, a calcium-activated cysteine protease, in a neuronal activity-dependent manner, predominantly via NMDA receptors or voltage-gated calcium channels. Furthermore, we clarified that 12K-CTF is generated by sequential cleavages at Q220 and S244. The amino-terminal fragment (NTF) of PRRT2, which corresponds to PKD-related truncated mutants, is not detected, probably due to rapid cleavage at multiple positions. Given that 12K-CTF lacks most of the proline-rich domain, this cleavage might be involved in the activity-dependent enhancement of neuronal excitation perhaps through transient retraction of PRRT2's function. Therefore, PRRT2 might serve as a buffer for neuronal excitation, and lack of this function in PKD patients might cause neuronal hyperexcitability in their motor circuits.

Keywords: NMDA receptor; calcium signaling; glutamate; neuronal excitation; proteolysis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calpain / metabolism*
  • Cells, Cultured
  • Cerebral Cortex / cytology*
  • Dyskinesias
  • Glutamic Acid / pharmacology
  • Male
  • Membrane Potentials
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / drug effects
  • Neurons / metabolism*
  • Plasmids

Substances

  • Membrane Proteins
  • Nerve Tissue Proteins
  • PRRT2 protein, human
  • PRRT2 protein, mouse
  • Glutamic Acid
  • Calpain