The Prion Protein Modulates A-type K+Currents Mediated by Kv4.2 Complexes through Dipeptidyl Aminopeptidase-like Protein 6

Robert C. C. Mercer, Li Ma, Joel C. Watts, Robert Strome, Serene Wohlgemuth, Jing Yang, Neil R. Cashman, Michael B. Coulthart, Gerold Schmitt-Ulms, Jack H. Jhamandas, David Westaway
2013 Journal of Biological Chemistry  
Prion protein (PrP) interacts with dipeptidyl aminopeptidase-like protein 6 (DPP6), but the functional significance was unknown. Results: PrP formed complexes with and impacted the function of potassium channels containing DPP6 and Kv4.2. Conclusion: PrP modulates voltage-dependent and kinetic properties of Kv4.2 channels. Significance: This could explain a phenotype of PrP knock-out mice and the effects of amyloid ␤ oligomers. Widely expressed in the adult central nervous system, the cellular
more » ... rion 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 Kv4.2based 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 DPP6dependent 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 A␤-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 A␤ upon neuronal excitability and viability.
doi:10.1074/jbc.m113.488650 pmid:24225951 pmcid:PMC3873577 fatcat:kndrklnq7rdrrfwwbrepcgtu4m