The prion protein modulates A-type K+ currents mediated by Kv4.2 complexes through dipeptidyl aminopeptidase-like protein 6

J Biol Chem. 2013 Dec 27;288(52):37241-55. doi: 10.1074/jbc.M113.488650. Epub 2013 Nov 13.


Widely expressed in the adult central nervous system, the cellular prion protein (PrP(C)) is implicated in a variety of processes, including neuronal excitability. Dipeptidyl aminopeptidase-like protein 6 (DPP6) was first identified as a PrP(C) interactor using in vivo formaldehyde cross-linking of wild type (WT) mouse brain. This finding was confirmed in three cell lines and, because DPP6 directs the functional assembly of K(+) channels, we assessed the impact of WT and mutant PrP(C) upon Kv4.2-based cell surface macromolecular complexes. Whereas a Gerstmann-Sträussler-Scheinker disease version of PrP with eight extra octarepeats was a loss of function both for complex formation and for modulation of Kv4.2 channels, WT PrP(C), in a DPP6-dependent manner, modulated Kv4.2 channel properties, causing an increase in peak amplitude, a rightward shift of the voltage-dependent steady-state inactivation curve, a slower inactivation, and a faster recovery from steady-state inactivation. Thus, the net impact of wt PrP(C) was one of enhancement, which plays a critical role in the down-regulation of neuronal membrane excitability and is associated with a decreased susceptibility to seizures. Insofar as previous work has established a requirement for WT PrP(C) in the Aβ-dependent modulation of excitability in cholinergic basal forebrain neurons, our findings implicate PrP(C) regulation of Kv4.2 channels as a mechanism contributing to the effects of oligomeric Aβ upon neuronal excitability and viability.

Keywords: Electrophysiology; Membrane Proteins; Potassium Channels; Prions; Protein Cross-linking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / genetics
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / metabolism*
  • HEK293 Cells
  • Humans
  • Membrane Potentials / physiology
  • Mice
  • Mice, Mutant Strains
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*
  • Potassium Channels / genetics
  • Potassium Channels / metabolism*
  • PrPC Proteins / genetics
  • PrPC Proteins / metabolism*
  • Prosencephalon / cytology
  • Prosencephalon / metabolism*
  • Shal Potassium Channels / genetics
  • Shal Potassium Channels / metabolism*


  • APP protein, human
  • Amyloid beta-Protein Precursor
  • Nerve Tissue Proteins
  • Potassium Channels
  • PrPC Proteins
  • Shal Potassium Channels
  • DPP6 protein, human
  • DPP6 protein, mouse
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases