The prion protein modulates A-type K+ currents mediated by Kv4.2 complexes through dipeptidyl aminopeptidase-like protein 6.
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.
From the Centre for Prions and Protein Folding Diseases.
Robert C C
RC
Mercer
Li
L
Ma
Joel C
JC
Watts
Robert
R
Strome
Serene
S
Wohlgemuth
Jing
J
Yang
Neil R
NR
Cashman
Michael B
MB
Coulthart
Gerold
G
Schmitt-Ulms
Jack H
JH
Jhamandas
David
D
Westaway
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism*; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism*
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D018621:PrPC Proteins; D051672:Shal Potassium Channels; C503535:DPP6 protein, human; C569992:DPP6 protein, mouse; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
Electrophysiology; Membrane Proteins; Potassium Channels; Prions; Protein Cross-linking