Abstract
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.
Highlights
Prion protein (PrP) interacts with dipeptidyl aminopeptidase-like protein 6 (DPP6), but the functional significance was unknown
When N2a cells expressing endogenous PrPC were transfected with plasmids encoding DPP6 (DPP6-S and DPP6-E) [23], cross-linked, and immunoprecipitated with 7A12 (␣-PrP) and membranes were probed with 03K1, a novel species was observed with a mobility of ϳ190 kDa (Fig. 1D)
These data indicate that PrPC is located in membrane subdomains that harbor dimeric DPP6 or that PrP and DPP6 exist in direct physical contact in a protein complex with a stoichiometry that totals to an Mr of ϳ190,000
Summary
Prion protein (PrP) interacts with dipeptidyl aminopeptidase-like protein 6 (DPP6), but the functional significance was unknown. Dipeptidyl aminopeptidase-like protein 6 (DPP6) was first identified as a PrPC 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 PrPC upon Kv4.2based cell surface macromolecular complexes. In addition to previously described interacting proteins, dipeptidyl aminopeptidase-like protein 6 (DPP6; known as DPPX) was identified using time-controlled transcardiac perfusion cross-linking while probing the PrPC interactome [19].
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