Advertisement

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

  • Robert C.C. Mercer
    Footnotes
    Affiliations
    Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta T6G 2M8, Canada

    Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta T6G 2M8, Canada
    Search for articles by this author
  • Li Ma
    Footnotes
    Affiliations
    Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta T6G 2M8, Canada

    Centre for Neuroscience, University of Alberta, Edmonton, Alberta T6G 2M8, Canada
    Search for articles by this author
  • Joel C. Watts
    Affiliations
    Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T2S8, Canada
    Search for articles by this author
  • Robert Strome
    Affiliations
    Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T2S8, Canada
    Search for articles by this author
  • Serene Wohlgemuth
    Affiliations
    Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta T6G 2M8, Canada

    Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta T6G 2M8, Canada
    Search for articles by this author
  • Jing Yang
    Affiliations
    Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta T6G 2M8, Canada
    Search for articles by this author
  • Neil R. Cashman
    Affiliations
    Division of Neurology, University of British Columbia, Vancouver, British Columbia V6T2B5, Canada
    Search for articles by this author
  • Michael B. Coulthart
    Affiliations
    Canadian Creutzfeldt-Jakob Disease Surveillance System, Public Health Agency of Canada, Ottawa, Ontario K1A0K9, Canada
    Search for articles by this author
  • Gerold Schmitt-Ulms
    Affiliations
    Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5T2S8, Canada
    Search for articles by this author
  • Jack H. Jhamandas
    Correspondence
    To whom correspondence may be addressed: 530 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Tel.: 780-407-7153; Fax: 780-407-3410
    Affiliations
    Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta T6G 2M8, Canada

    Centre for Neuroscience, University of Alberta, Edmonton, Alberta T6G 2M8, Canada
    Search for articles by this author
  • David Westaway
    Correspondence
    To whom correspondence may be addressed: Centre for Prions and Protein Folding Diseases, 2-04 Brain and Aging Research Bldg., University of Alberta, Edmonton, Alberta T6G 2M8, Canada. Tel.: 780-492-9377; Fax: 780-492-9352;
    Affiliations
    Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta T6G 2M8, Canada

    Department of Medicine (Neurology), University of Alberta, Edmonton, Alberta T6G 2M8, Canada

    Centre for Neuroscience, University of Alberta, Edmonton, Alberta T6G 2M8, Canada

    Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2M8, Canada
    Search for articles by this author
  • Author Footnotes
    * This work was supported by grants from the PrioNet Network Centres of Excellence, Alberta Prion Research Institute Grant APRI 200600070, Alberta Innovates-Health Solutions Grant AHFMR 201000628, Canadian Institutes of Health Research Grants MOP36377 and 93601, and the Canadian Foundation for Innovation.
    1 Both authors contributed equally to this work.
    2 Recipient of Alberta Innovates-Health Solutions Scholarship AHFMR 201100104.
Open AccessPublished:November 13, 2013DOI:https://doi.org/10.1074/jbc.M113.488650
      Widely expressed in the adult central nervous system, the cellular prion protein (PrPC) is implicated in a variety of processes, including neuronal excitability. 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 Kv4.2-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 PrPC, 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 PrPC 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 PrPC in the Aβ-dependent modulation of excitability in cholinergic basal forebrain neurons, our findings implicate PrPC regulation of Kv4.2 channels as a mechanism contributing to the effects of oligomeric Aβ upon neuronal excitability and viability.

      Introduction

      Prion diseases involve the structural conversion of the primarily α-helical, cellular prion protein (PrPC)
      The abbreviations used are: PrPC
      cellular prion protein
      PrP
      prion protein
      DPP6
      dipeptidyl aminopeptidase-like protein 6
      KChIP
      K+ channel-interacting protein.
      to an infectious, β-sheet-enriched form, PrPSc. The high degree of primary to tertiary structural conservation of mammalian PrPC (
      • Wopfner F.
      • Weidenhöfer G.
      • Schneider R.
      • von Brunn A.
      • Gilch S.
      • Schwarz T.F.
      • Werner T.
      • Schätzl H.M.
      Analysis of 27 mammalian and 9 avian PrPs reveals high conservation of flexible regions of the prion protein.
      ,
      • Calzolai L.
      • Lysek D.A.
      • Pérez D.R.
      • Güntert P.
      • Wüthrich K.
      Prion protein NMR structures of chickens, turtles, and frogs.
      ) leads to an expectation of an explicit phenotype in Prnp0/0 mice, but, aside from a total resistance to prion disease, this is not the case (
      • Büeler H.
      • Fischer M.
      • Lang Y.
      • Bluethmann H.
      • Lipp H.P.
      • DeArmond S.J.
      • Prusiner S.B.
      • Aguet M.
      • Weissmann C.
      Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein.
      ,
      • Manson J.C.
      • Clarke A.R.
      • Hooper M.L.
      • Aitchison L.
      • McConnell I.
      • Hope J.
      129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal.
      ). That said, within the inventory of subtle or disputed phenotypic changes in these mice are reports of impairment in GABAA receptor-mediated inhibition and long term potentiation (
      • Collinge J.
      • Whittington M.A.
      • Sidle K.C.
      • Smith C.J.
      • Palmer M.S.
      • Clarke A.R.
      • Jefferys J.G.
      Prion protein is necessary for normal synaptic function.
      ,
      • Whittington M.A.
      • Sidle K.C.
      • Gowland I.
      • Meads J.
      • Hill A.F.
      • Palmer M.S.
      • Jefferys J.G.
      • Collinge J.
      Rescue of neurophysiological phenotype seen in PrP null mice by transgene encoding human prion protein.
      ,
      • Manson J.C.
      • Hope J.
      • Clarke A.R.
      • Johnston A.
      • Black C.
      • MacLeod N.
      PrP gene dosage and long term potentiation.
      ,
      • Curtis J.
      • Errington M.
      • Bliss T.
      • Voss K.
      • MacLeod N.
      Age-dependent loss of PTP and LTP in the hippocampus of PrP-null mice.
      ). The diversity of altered end point measures is, to a certain extent, paralleled in the large number of reported PrPC-interacting proteins: the laminin receptor (
      • Rieger R.
      • Edenhofer F.
      • Lasmézas C.I.
      • Weiss S.
      The human 37-kDa laminin receptor precursor interacts with the prion protein in eukaryotic cells.
      ,
      • Gauczynski S.
      • Peyrin J.M.
      • Haïk S.
      • Leucht C.
      • Hundt C.
      • Rieger R.
      • Krasemann S.
      • Deslys J.P.
      • Dormont D.
      • Lasmézas C.I.
      • Weiss S.
      The 37-kDa/67-kDa laminin receptor acts as the cell-surface receptor for the cellular prion protein.
      ,
      • Hundt C.
      • Peyrin J.M.
      • Haïk S.
      • Gauczynski S.
      • Leucht C.
      • Rieger R.
      • Riley M.L.
      • Deslys J.P.
      • Dormont D.
      • Lasmézas C.I.
      • Weiss S.
      Identification of interaction domains of the prion protein with its 37-kDa/67-kDa laminin receptor.
      ), the neural cell adhesion molecule (
      • Schmitt-Ulms G.
      • Legname G.
      • Baldwin M.A.
      • Ball H.L.
      • Bradon N.
      • Bosque P.J.
      • Crossin K.L.
      • Edelman G.M.
      • DeArmond S.J.
      • Cohen F.E.
      • Prusiner S.B.
      Binding of neural cell adhesion molecules (N-CAMs) to the cellular prion protein.
      ,
      • Santuccione A.
      • Sytnyk V.
      • Leshchyns'ka I.
      • Schachner M.
      Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth.
      ), stress-inducible protein-1 (
      • Zanata S.M.
      • Lopes M.H.
      • Mercadante A.F.
      • Hajj G.N.
      • Chiarini L.B.
      • Nomizo R.
      • Freitas A.R.
      • Cabral A.L.
      • Lee K.S.
      • Juliano M.A.
      • de Oliveira E.
      • Jachieri S.G.
      • Burlingame A.
      • Huang L.
      • Linden R.
      • Brentani R.R.
      • Martins V.R.
      Stress-inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection.
      ,
      • Roffé M.
      • Beraldo F.H.
      • Bester R.
      • Nunziante M.
      • Bach C.
      • Mancini G.
      • Gilch S.
      • Vorberg I.
      • Castilho B.A.
      • Martins V.R.
      • Hajj G.N.
      Prion protein interaction with stress-inducible protein 1 enhances neuronal protein synthesis via mTOR.
      ), and NMDA receptors (
      • Khosravani H.
      • Zhang Y.
      • Tsutsui S.
      • Hameed S.
      • Altier C.
      • Hamid J.
      • Chen L.
      • Villemaire M.
      • Ali Z.
      • Jirik F.R.
      • Zamponi G.W.
      Prion protein attenuates excitotoxicity by inhibiting NMDA receptors.
      ,
      • You H.
      • Tsutsui S.
      • Hameed S.
      • Kannanayakal T.J.
      • Chen L.
      • Xia P.
      • Engbers J.D.
      • Lipton S.A.
      • Stys P.K.
      • Zamponi G.W.
      Abeta neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-d-aspartate receptors.
      ) to name but a few (reviewed in Ref.
      • Watts J.C.
      • Westaway D.
      The prion protein family. Diversity, rivalry, and dysfunction.
      ).
      In addition to previously described interacting proteins, dipeptidyl aminopeptidase-like protein 6 (DPP6; also known as DPPX) was identified using time-controlled transcardiac perfusion cross-linking while probing the PrPC interactome (
      • Schmitt-Ulms G.
      • Hansen K.
      • Liu J.
      • Cowdrey C.
      • Yang J.
      • DeArmond S.J.
      • Cohen F.E.
      • Prusiner S.B.
      • Baldwin M.A.
      Time-controlled transcardiac perfusion cross-linking for the study of protein interactions in complex tissues.
      ). DPP6 is an auxiliary subunit of pore-forming Kv4.2 channels (
      • Nadal M.S.
      • Ozaita A.
      • Amarillo Y.
      • Vega-Saenz de Miera E.
      • Ma Y.
      • Mo W.
      • Goldberg E.M.
      • Misumi Y.
      • Ikehara Y.
      • Neubert T.A.
      • Rudy B.
      The CD26-related dipeptidyl aminopeptidase-like protein DPPX is a critical component of neuronal A-type K+ channels.
      ,
      • Kim J.
      • Nadal M.S.
      • Clemens A.M.
      • Baron M.
      • Jung S.C.
      • Misumi Y.
      • Rudy B.
      • Hoffman D.A.
      Kv4 accessory protein DPPX (DPP6) is a critical regulator of membrane excitability in hippocampal CA1 pyramidal neurons.
      ) and, together with most K+ channel-interacting protein (KChIP) isoforms (
      • An W.F.
      • Bowlby M.R.
      • Betty M.
      • Cao J.
      • Ling H.P.
      • Mendoza G.
      • Hinson J.W.
      • Mattsson K.I.
      • Strassle B.W.
      • Trimmer J.S.
      • Rhodes K.J.
      Modulation of A-type potassium channels by a family of calcium sensors.
      ), DPP6 increases Kv4.2 trafficking to the cell surface and is required for the reconstitution of the properties of the native channel complex in heterologous cells (
      • Seikel E.
      • Trimmer J.S.
      Convergent modulation of Kv4.2 channel α subunits by structurally distinct DPPX and KChIP auxiliary subunits.
      ). A type II transmembrane protein, DPP6 has a number of splice variants differing in the length of the cytoplasmic, N-terminal portion (DPP6-S; short) (
      • Maffie J.
      • Blenkinsop T.
      • Rudy B.
      A novel DPP6 isoform (DPP6-E) can account for differences between neuronal and reconstituted A-type K+ channels.
      ). KChIPs are a family of intracellular Ca2+-binding proteins with four major isoforms (
      • Wopfner F.
      • Weidenhöfer G.
      • Schneider R.
      • von Brunn A.
      • Gilch S.
      • Schwarz T.F.
      • Werner T.
      • Schätzl H.M.
      Analysis of 27 mammalian and 9 avian PrPs reveals high conservation of flexible regions of the prion protein.
      ,
      • Calzolai L.
      • Lysek D.A.
      • Pérez D.R.
      • Güntert P.
      • Wüthrich K.
      Prion protein NMR structures of chickens, turtles, and frogs.
      ,
      • Büeler H.
      • Fischer M.
      • Lang Y.
      • Bluethmann H.
      • Lipp H.P.
      • DeArmond S.J.
      • Prusiner S.B.
      • Aguet M.
      • Weissmann C.
      Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein.
      ,
      • Manson J.C.
      • Clarke A.R.
      • Hooper M.L.
      • Aitchison L.
      • McConnell I.
      • Hope J.
      129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal.
      ) and at least 16 splice variants (
      • Pruunsild P.
      • Timmusk T.
      Structure, alternative splicing, and expression of the human and mouse KCNIP gene family.
      ). Interactions between Kv4.2, KChIPs and DPP6 have been confirmed by proteomic analyses demonstrating the pull-down of KChIP1 to -3 in comparable ratios (
      • Marionneau C.
      • LeDuc R.D.
      • Rohrs H.W.
      • Link A.J.
      • Townsend R.R.
      • Nerbonne J.M.
      Proteomic analyses of native brain KV4.2 channel complexes.
      ). Assembled Kv4 channel complexes mediate sub-threshold operation somatodendritic transient outward K+ currents (A-type K+ currents), which play important roles in the regulation of neuronal membrane excitability, somatodendritic signal integration, and long term potentiation (
      • Birnbaum S.G.
      • Varga A.W.
      • Yuan L.L.
      • Anderson A.E.
      • Sweatt J.D.
      • Schrader L.A.
      Structure and function of Kv4-family transient potassium channels.
      ,
      • Johnston D.
      • Christie B.R.
      • Frick A.
      • Gray R.
      • Hoffman D.A.
      • Schexnayder L.K.
      • Watanabe S.
      • Yuan L.L.
      Active dendrites, potassium channels and synaptic plasticity.
      ). Given the interplay between Kv4.2 channels and DPP6 in neuronal function (
      • Sun W.
      • Maffie J.K.
      • Lin L.
      • Petralia R.S.
      • Rudy B.
      • Hoffman D.A.
      DPP6 establishes the A-type K+ current gradient critical for the regulation of dendritic excitability in CA1 hippocampal neurons.
      ) and the ability to cross-link DPP6 and PrPC in vivo (
      • Schmitt-Ulms G.
      • Hansen K.
      • Liu J.
      • Cowdrey C.
      • Yang J.
      • DeArmond S.J.
      • Cohen F.E.
      • Prusiner S.B.
      • Baldwin M.A.
      Time-controlled transcardiac perfusion cross-linking for the study of protein interactions in complex tissues.
      ), we sought to delineate the nature and repercussions of a DPP6-PrPC interaction. To this end, we investigated the impact of PrPC upon the properties of A-type K+ currents mediated by Kv4.2 channel complexes derived from co-expression of Kv4.2, KChIP2, and DPP6-S (
      • Lundby A.
      • Jespersen T.
      • Schmitt N.
      • Grunnet M.
      • Olesen S.P.
      • Cordeiro J.M.
      • Calloe K.
      Effect of the I(to) activator NS5806 on cloned KV4 channels depends on the accessory protein KChIP2.
      ,
      • Witzel K.
      • Fischer P.
      • Bähring R.
      Hippocampal A-type current and Kv4.2 channel modulation by the sulfonylurea compound NS5806.
      ).

      Acknowledgments

      DPP6df5J/Rw mice were a generous gift from Dr. John Schimenti, and we thank Dr. Nam-Chaing Wang (Hospital for Sick Children, Toronto, Canada) for peptide syntheses. α-Thy-1 was a gift from Dr. Roger Morris (King's College, London).

      REFERENCES

        • Wopfner F.
        • Weidenhöfer G.
        • Schneider R.
        • von Brunn A.
        • Gilch S.
        • Schwarz T.F.
        • Werner T.
        • Schätzl H.M.
        Analysis of 27 mammalian and 9 avian PrPs reveals high conservation of flexible regions of the prion protein.
        J. Mol. Biol. 1999; 289: 1163-1178
        • Calzolai L.
        • Lysek D.A.
        • Pérez D.R.
        • Güntert P.
        • Wüthrich K.
        Prion protein NMR structures of chickens, turtles, and frogs.
        Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 651-655
        • Büeler H.
        • Fischer M.
        • Lang Y.
        • Bluethmann H.
        • Lipp H.P.
        • DeArmond S.J.
        • Prusiner S.B.
        • Aguet M.
        • Weissmann C.
        Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein.
        Nature. 1992; 356: 577-582
        • Manson J.C.
        • Clarke A.R.
        • Hooper M.L.
        • Aitchison L.
        • McConnell I.
        • Hope J.
        129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal.
        Mol. Neurobiol. 1994; 8: 121-127
        • Collinge J.
        • Whittington M.A.
        • Sidle K.C.
        • Smith C.J.
        • Palmer M.S.
        • Clarke A.R.
        • Jefferys J.G.
        Prion protein is necessary for normal synaptic function.
        Nature. 1994; 370: 295-297
        • Whittington M.A.
        • Sidle K.C.
        • Gowland I.
        • Meads J.
        • Hill A.F.
        • Palmer M.S.
        • Jefferys J.G.
        • Collinge J.
        Rescue of neurophysiological phenotype seen in PrP null mice by transgene encoding human prion protein.
        Nat. Genet. 1995; 9: 197-201
        • Manson J.C.
        • Hope J.
        • Clarke A.R.
        • Johnston A.
        • Black C.
        • MacLeod N.
        PrP gene dosage and long term potentiation.
        Neurodegeneration. 1995; 4: 113-114
        • Curtis J.
        • Errington M.
        • Bliss T.
        • Voss K.
        • MacLeod N.
        Age-dependent loss of PTP and LTP in the hippocampus of PrP-null mice.
        Neurobiol. Dis. 2003; 13: 55-62
        • Rieger R.
        • Edenhofer F.
        • Lasmézas C.I.
        • Weiss S.
        The human 37-kDa laminin receptor precursor interacts with the prion protein in eukaryotic cells.
        Nat. Med. 1997; 3: 1383-1388
        • Gauczynski S.
        • Peyrin J.M.
        • Haïk S.
        • Leucht C.
        • Hundt C.
        • Rieger R.
        • Krasemann S.
        • Deslys J.P.
        • Dormont D.
        • Lasmézas C.I.
        • Weiss S.
        The 37-kDa/67-kDa laminin receptor acts as the cell-surface receptor for the cellular prion protein.
        EMBO J. 2001; 20: 5863-5875
        • Hundt C.
        • Peyrin J.M.
        • Haïk S.
        • Gauczynski S.
        • Leucht C.
        • Rieger R.
        • Riley M.L.
        • Deslys J.P.
        • Dormont D.
        • Lasmézas C.I.
        • Weiss S.
        Identification of interaction domains of the prion protein with its 37-kDa/67-kDa laminin receptor.
        EMBO J. 2001; 20: 5876-5886
        • Schmitt-Ulms G.
        • Legname G.
        • Baldwin M.A.
        • Ball H.L.
        • Bradon N.
        • Bosque P.J.
        • Crossin K.L.
        • Edelman G.M.
        • DeArmond S.J.
        • Cohen F.E.
        • Prusiner S.B.
        Binding of neural cell adhesion molecules (N-CAMs) to the cellular prion protein.
        J. Mol. Biol. 2001; 314: 1209-1225
        • Santuccione A.
        • Sytnyk V.
        • Leshchyns'ka I.
        • Schachner M.
        Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth.
        J. Cell Biol. 2005; 169: 341-354
        • Zanata S.M.
        • Lopes M.H.
        • Mercadante A.F.
        • Hajj G.N.
        • Chiarini L.B.
        • Nomizo R.
        • Freitas A.R.
        • Cabral A.L.
        • Lee K.S.
        • Juliano M.A.
        • de Oliveira E.
        • Jachieri S.G.
        • Burlingame A.
        • Huang L.
        • Linden R.
        • Brentani R.R.
        • Martins V.R.
        Stress-inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection.
        EMBO J. 2002; 21: 3307-3316
        • Roffé M.
        • Beraldo F.H.
        • Bester R.
        • Nunziante M.
        • Bach C.
        • Mancini G.
        • Gilch S.
        • Vorberg I.
        • Castilho B.A.
        • Martins V.R.
        • Hajj G.N.
        Prion protein interaction with stress-inducible protein 1 enhances neuronal protein synthesis via mTOR.
        Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 13147-13152
        • Khosravani H.
        • Zhang Y.
        • Tsutsui S.
        • Hameed S.
        • Altier C.
        • Hamid J.
        • Chen L.
        • Villemaire M.
        • Ali Z.
        • Jirik F.R.
        • Zamponi G.W.
        Prion protein attenuates excitotoxicity by inhibiting NMDA receptors.
        J. Gen. Physiol. 2008; 131: i5
        • You H.
        • Tsutsui S.
        • Hameed S.
        • Kannanayakal T.J.
        • Chen L.
        • Xia P.
        • Engbers J.D.
        • Lipton S.A.
        • Stys P.K.
        • Zamponi G.W.
        Abeta neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-d-aspartate receptors.
        Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 1737-1742
        • Watts J.C.
        • Westaway D.
        The prion protein family. Diversity, rivalry, and dysfunction.
        Biochim. Biophys. Acta. 2007; 1772: 654-672
        • Schmitt-Ulms G.
        • Hansen K.
        • Liu J.
        • Cowdrey C.
        • Yang J.
        • DeArmond S.J.
        • Cohen F.E.
        • Prusiner S.B.
        • Baldwin M.A.
        Time-controlled transcardiac perfusion cross-linking for the study of protein interactions in complex tissues.
        Nat. Biotechnol. 2004; 22: 724-731
        • Nadal M.S.
        • Ozaita A.
        • Amarillo Y.
        • Vega-Saenz de Miera E.
        • Ma Y.
        • Mo W.
        • Goldberg E.M.
        • Misumi Y.
        • Ikehara Y.
        • Neubert T.A.
        • Rudy B.
        The CD26-related dipeptidyl aminopeptidase-like protein DPPX is a critical component of neuronal A-type K+ channels.
        Neuron. 2003; 37: 449-461
        • Kim J.
        • Nadal M.S.
        • Clemens A.M.
        • Baron M.
        • Jung S.C.
        • Misumi Y.
        • Rudy B.
        • Hoffman D.A.
        Kv4 accessory protein DPPX (DPP6) is a critical regulator of membrane excitability in hippocampal CA1 pyramidal neurons.
        J. Neurophysiol. 2008; 100: 1835-1847
        • An W.F.
        • Bowlby M.R.
        • Betty M.
        • Cao J.
        • Ling H.P.
        • Mendoza G.
        • Hinson J.W.
        • Mattsson K.I.
        • Strassle B.W.
        • Trimmer J.S.
        • Rhodes K.J.
        Modulation of A-type potassium channels by a family of calcium sensors.
        Nature. 2000; 403: 553-556
        • Seikel E.
        • Trimmer J.S.
        Convergent modulation of Kv4.2 channel α subunits by structurally distinct DPPX and KChIP auxiliary subunits.
        Biochemistry. 2009; 48: 5721-5730
        • Maffie J.
        • Blenkinsop T.
        • Rudy B.
        A novel DPP6 isoform (DPP6-E) can account for differences between neuronal and reconstituted A-type K+ channels.
        Neurosci. Lett. 2009; 449: 189-194
        • Pruunsild P.
        • Timmusk T.
        Structure, alternative splicing, and expression of the human and mouse KCNIP gene family.
        Genomics. 2005; 86: 581-593
        • Marionneau C.
        • LeDuc R.D.
        • Rohrs H.W.
        • Link A.J.
        • Townsend R.R.
        • Nerbonne J.M.
        Proteomic analyses of native brain KV4.2 channel complexes.
        Channels. 2009; 3: 284-294
        • Birnbaum S.G.
        • Varga A.W.
        • Yuan L.L.
        • Anderson A.E.
        • Sweatt J.D.
        • Schrader L.A.
        Structure and function of Kv4-family transient potassium channels.
        Physiol. Rev. 2004; 84: 803-833
        • Johnston D.
        • Christie B.R.
        • Frick A.
        • Gray R.
        • Hoffman D.A.
        • Schexnayder L.K.
        • Watanabe S.
        • Yuan L.L.
        Active dendrites, potassium channels and synaptic plasticity.
        Philos. Trans. R. Soc. Lond. B Biol. Sci. 2003; 358: 667-674
        • Sun W.
        • Maffie J.K.
        • Lin L.
        • Petralia R.S.
        • Rudy B.
        • Hoffman D.A.
        DPP6 establishes the A-type K+ current gradient critical for the regulation of dendritic excitability in CA1 hippocampal neurons.
        Neuron. 2011; 71: 1102-1115
        • Lundby A.
        • Jespersen T.
        • Schmitt N.
        • Grunnet M.
        • Olesen S.P.
        • Cordeiro J.M.
        • Calloe K.
        Effect of the I(to) activator NS5806 on cloned KV4 channels depends on the accessory protein KChIP2.
        Br. J. Pharmacol. 2010; 160: 2028-2044
        • Witzel K.
        • Fischer P.
        • Bähring R.
        Hippocampal A-type current and Kv4.2 channel modulation by the sulfonylurea compound NS5806.
        Neuropharmacology. 2012; 63: 1389-1403
        • Chomczynski P.
        • Sacchi N.
        Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
        Anal. Biochem. 1987; 162: 156-159
        • Drisaldi B.
        • Coomaraswamy J.
        • Mastrangelo P.
        • Strome B.
        • Yang J.
        • Watts J.C.
        • Chishti M.A.
        • Marvi M.
        • Windl O.
        • Ahrens R.
        • Major F.
        • Sy M.S.
        • Kretzschmar H.
        • Fraser P.E.
        • Mount H.T.
        • Westaway D.
        Genetic mapping of activity determinants within cellular prion proteins. N-terminal modules in PrPC offset pro-apoptotic activity of the Doppel helix B/B′ region.
        J. Biol. Chem. 2004; 279: 55443-55454
        • Hough R.B.
        • Lengeling A.
        • Bedian V.
        • Lo C.
        • Bućan M.
        Rump white inversion in the mouse disrupts dipeptidyl aminopeptidase-like protein 6 and causes dysregulation of Kit expression.
        Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 13800-13805
        • Strop P.
        • Bankovich A.J.
        • Hansen K.C.
        • Garcia K.C.
        • Brunger A.T.
        Structure of a human A-type potassium channel interacting protein DPPX, a member of the dipeptidyl aminopeptidase family.
        J. Mol. Biol. 2004; 343: 1055-1065
        • Clark B.D.
        • Kwon E.
        • Maffie J.
        • Jeong H.Y.
        • Nadal M.
        • Strop P.
        • Rudy B.
        DPP6 localization in brain supports function as a Kv4 channel associated protein.
        Front. Mol. Neurosci. 2008; 1: 8
        • Homans S.W.
        • Ferguson M.A.
        • Dwek R.A.
        • Rademacher T.W.
        • Anand R.
        • Williams A.F.
        Complete structure of the glycosyl phosphatidylinositol membrane anchor of rat brain Thy-1 glycoprotein.
        Nature. 1988; 333: 269-272
        • Riek R.
        • Hornemann S.
        • Wider G.
        • Billeter M.
        • Glockshuber R.
        • Wüthrich K.
        NMR structure of the mouse prion protein domain PrP(121–231).
        Nature. 1996; 382: 180-182
        • Riek R.
        • Hornemann S.
        • Wider G.
        • Glockshuber R.
        • Wüthrich K.
        NMR characterization of the full-length recombinant murine prion protein, mPrP(23–231).
        FEBS Lett. 1997; 413: 282-288
        • Mo H.
        • Moore R.C.
        • Cohen F.E.
        • Westaway D.
        • Prusiner S.B.
        • Wright P.E.
        • Dyson H.J.
        Two different neurodegenerative diseases caused by proteins with similar structures.
        Proc. Natl. Acad. Sci. U.S.A. 2001; 98: 2352-2357
        • Laplanche J.L.
        • Hachimi K.H.
        • Durieux I.
        • Thuillet P.
        • Defebvre L.
        • Delasnerie-Laupretre N.
        • Peoc'h K.
        • Foncin J.F.
        • Destee A.
        Prominent psychiatric features and early onset in an inherited prion disease with a new insertional mutation in the prion protein gene.
        Brain. 1999; 122: 2375-2386
        • Doh-ura K.
        • Tateishi J.
        • Sasaki H.
        • Kitamoto T.
        • Sakaki Y.
        Pro–Leu change at position 102 of prion protein is the most common but not the sole mutation related to Gerstmann-Straussler syndrome.
        Biochem. Biophys. Res. Commun. 1989; 163: 974-979
        • Hsiao K.K.
        • Cass C.
        • Schellenberg G.D.
        • Bird T.
        • Devine-Gage E.
        • Wisniewski H.
        • Prusiner S.B.
        A prion protein variant in a family with the telencephalic form of Gerstmann-Straussler-Scheinker syndrome.
        Neurology. 1991; 41: 681-684
        • Hinnell C.
        • Coulthart M.B.
        • Jansen G.H.
        • Cashman N.R.
        • Lauzon J.
        • Clark A.
        • Costello F.
        • White C.
        • Midha R.
        • Wiebe S.
        • Furtado S.
        Gerstmann-Straussler-Scheinker disease due to a novel prion protein gene mutation.
        Neurology. 2011; 76: 485-487
        • Oesch B.
        • Westaway D.
        • Wälchli M.
        • McKinley M.P.
        • Kent S.B.
        • Aebersold R.
        • Barry R.A.
        • Tempst P.
        • Teplow D.B.
        • Hood L.E.
        A cellular gene encodes scrapie PrP 27–30 protein.
        Cell. 1985; 40: 735-746
        • Kretzschmar H.A.
        • Prusiner S.B.
        • Stowring L.E.
        • DeArmond S.J.
        Scrapie prion proteins are synthesized in neurons.
        Am. J. Pathol. 1986; 122: 1-5
        • Peralta O.A.
        • Eyestone W.H.
        Quantitative and qualitative analysis of cellular prion protein (PrP(C)) expression in bovine somatic tissues.
        Prion. 2009; 3: 161-170
        • Herms J.W.
        • Tings T.
        • Dunker S.
        • Kretzschmar H.A.
        Prion protein affects Ca2+-activated K+ currents in cerebellar purkinje cells.
        Neurobiol. Dis. 2001; 8: 324-330
        • Carleton A.
        • Tremblay P.
        • Vincent J.D.
        • Lledo P.M.
        Dose-dependent, prion protein (PrP)-mediated facilitation of excitatory synaptic transmission in the mouse hippocampus.
        Pflugers Arch. 2001; 442: 223-229
        • Mallucci G.R.
        • Ratté S.
        • Asante E.A.
        • Linehan J.
        • Gowland I.
        • Jefferys J.G.
        • Collinge J.
        Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration.
        EMBO J. 2002; 21: 202-210
        • Prestori F.
        • Rossi P.
        • Bearzatto B.
        • Lainé J.
        • Necchi D.
        • Diwakar S.
        • Schiffmann S.N.
        • Axelrad H.
        • D'Angelo E.
        Altered neuron excitability and synaptic plasticity in the cerebellar granular layer of juvenile prion protein knock-out mice with impaired motor control.
        J. Neurosci. 2008; 28: 7091-7103
        • Yu S.P.
        • Kerchner G.A.
        Endogenous voltage-gated potassium channels in human embryonic kidney (HEK293) cells.
        J. Neurosci. Res. 1998; 52: 612-617
        • Jiang B.
        • Sun X.
        • Cao K.
        • Wang R.
        Endogenous Kv channels in human embryonic kidney (HEK-293) cells.
        Mol. Cell. Biochem. 2002; 238: 69-79
        • Solomon I.H.
        • Huettner J.E.
        • Harris D.A.
        Neurotoxic mutants of the prion protein induce spontaneous ionic currents in cultured cells.
        J. Biol. Chem. 2010; 285: 26719-26726
        • Solomon I.H.
        • Khatri N.
        • Biasini E.
        • Massignan T.
        • Huettner J.E.
        • Harris D.A.
        An N-terminal polybasic domain and cell surface localization are required for mutant prion protein toxicity.
        J. Biol. Chem. 2011; 286: 14724-14736
        • Colling S.B.
        • Collinge J.
        • Jefferys J.G.
        Hippocampal slices from prion protein null mice. Disrupted Ca2+-activated K+ currents.
        Neurosci. Lett. 1996; 209: 49-52
        • Powell A.D.
        • Toescu E.C.
        • Collinge J.
        • Jefferys J.G.
        Alterations in Ca2+-buffering in prion-null mice. Association with reduced afterhyperpolarizations in CA1 hippocampal neurons.
        J. Neurosci. 2008; 28: 3877-3886
        • Beraldo F.H.
        • Arantes C.P.
        • Santos T.G.
        • Queiroz N.G.
        • Young K.
        • Rylett R.J.
        • Markus R.P.
        • Prado M.A.
        • Martins V.R.
        Role of α7 nicotinic acetylcholine receptor in calcium signaling induced by prion protein interaction with stress-inducible protein 1.
        J. Biol. Chem. 2010; 285: 36542-36550
        • Watt N.T.
        • Taylor D.R.
        • Kerrigan T.L.
        • Griffiths H.H.
        • Rushworth J.V.
        • Whitehouse I.J.
        • Hooper N.M.
        Prion protein facilitates uptake of zinc into neuronal cells.
        Nat. Commun. 2012; 3: 1134
        • Hornemann S.
        • Korth C.
        • Oesch B.
        • Riek R.
        • Wider G.
        • Wüthrich K.
        • Glockshuber R.
        Recombinant full-length murine prion protein, mPrP(23–231). Purification and spectroscopic characterization.
        FEBS Lett. 1997; 413: 277-281
        • Muramoto T.
        • DeArmond S.J.
        • Scott M.
        • Telling G.C.
        • Cohen F.E.
        • Prusiner S.B.
        Heritable disorder resembling neuronal storage disease in mice expressing prion protein with deletion of an α-helix.
        Nat. Med. 1997; 3: 750-755
        • Watts J.C.
        • Huo H.
        • Bai Y.
        • Ehsani S.
        • Jeon A.H.
        • Won A.H.
        • Shi T.
        • Daude N.
        • Lau A.
        • Young R.
        • Xu L.
        • Carlson G.A.
        • Williams D.
        • Westaway D.
        • Schmitt-Ulms G.
        Interactome analyses identify ties of PrP and its mammalian paralogs to oligomannosidic N-glycans and endoplasmic reticulum-derived chaperones.
        PLoS Pathog. 2009; 5: e1000608
        • Ren X.
        • Hayashi Y.
        • Yoshimura N.
        • Takimoto K.
        Transmembrane interaction mediates complex formation between peptidase homologues and Kv4 channels.
        Mol. Cell. Neurosci. 2005; 29: 320-332
        • Linden R.
        • Martins V.R.
        • Prado M.A.
        • Cammarota M.
        • Izquierdo I.
        • Brentani R.R.
        Physiology of the prion protein.
        Physiol. Rev. 2008; 88: 673-728
        • Parkin E.T.
        • Watt N.T.
        • Hussain I.
        • Eckman E.A.
        • Eckman C.B.
        • Manson J.C.
        • Baybutt H.N.
        • Turner A.J.
        • Hooper N.M.
        Cellular prion protein regulates β-secretase cleavage of the Alzheimer's amyloid precursor protein.
        Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 11062-11067
        • McHugh P.C.
        • Wright J.A.
        • Williams R.J.
        • Brown D.R.
        Prion protein expression alters APP cleavage without interaction with BACE-1.
        Neurochem. Int. 2012; 61: 672-680
        • Noor A.
        • Whibley A.
        • Marshall C.R.
        • Gianakopoulos P.J.
        • Piton A.
        • Carson A.R.
        • Orlic-Milacic M.
        • Lionel A.C.
        • Sato D.
        • Pinto D.
        • Drmic I.
        • Noakes C.
        • Senman L.
        • Zhang X.
        • Mo R.
        • Gauthier J.
        • Crosbie J.
        • Pagnamenta A.T.
        • Munson J.
        • Estes A.M.
        • Fiebig A.
        • Franke A.
        • Schreiber S.
        • Stewart A.F.
        • Roberts R.
        • McPherson R.
        • Guter S.J.
        • Cook Jr., E.H.
        • Dawson G.
        • Schellenberg G.D.
        • Battaglia A.
        • Maestrini E.
        • Jeng L.
        • Hutchison T.
        • Rajcan-Separovic E.
        • Chudley A.E.
        • Lewis S.M.
        • Liu X.
        • Holden J.J.
        • Fernandez B.
        • Zwaigenbaum L.
        • Bryson S.E.
        • Roberts W.
        • Szatmari P.
        • Gallagher L.
        • Stratton M.R.
        • Gecz J.
        • Brady A.F.
        • Schwartz C.E.
        • Schachar R.J.
        • Monaco A.P.
        • Rouleau G.A.
        • Hui C.C.
        • Lucy Raymond F.
        • Scherer S.W.
        • Vincent J.B.
        • Autism Genome Project Consortium
        Disruption at the PTCHD1 locus on Xp22.11 in autism spectrum disorder and intellectual disability.
        Sci. Transl. Med. 2010; 2: 49ra68
        • Marshall C.R.
        • Noor A.
        • Vincent J.B.
        • Lionel A.C.
        • Feuk L.
        • Skaug J.
        • Shago M.
        • Moessner R.
        • Pinto D.
        • Ren Y.
        • Thiruvahindrapduram B.
        • Fiebig A.
        • Schreiber S.
        • Friedman J.
        • Ketelaars C.E.
        • Vos Y.J.
        • Ficicioglu C.
        • Kirkpatrick S.
        • Nicolson R.
        • Sloman L.
        • Summers A.
        • Gibbons C.A.
        • Teebi A.
        • Chitayat D.
        • Weksberg R.
        • Thompson A.
        • Vardy C.
        • Crosbie V.
        • Luscombe S.
        • Baatjes R.
        • Zwaigenbaum L.
        • Roberts W.
        • Fernandez B.
        • Szatmari P.
        • Scherer S.W.
        Structural variation of chromosomes in autism spectrum disorder.
        Am. J. Hum. Genet. 2008; 82: 477-488
        • van Es M.A.
        • van Vught P.W.
        • Blauw H.M.
        • Franke L.
        • Saris C.G.
        • Van den Bosch L.
        • de Jong S.W.
        • de Jong V.
        • Baas F.
        • van't Slot R.
        • Lemmens R.
        • Schelhaas H.J.
        • Birve A.
        • Sleegers K.
        • Van Broeckhoven C.
        • Schymick J.C.
        • Traynor B.J.
        • Wokke J.H.
        • Wijmenga C.
        • Robberecht W.
        • Andersen P.M.
        • Veldink J.H.
        • Ophoff R.A.
        • van den Berg L.H.
        Genetic variation in DPP6 is associated with susceptibility to amyotrophic lateral sclerosis.
        Nat. Genet. 2008; 40: 29-31
        • Cronin S.
        • Berger S.
        • Ding J.
        • Schymick J.C.
        • Washecka N.
        • Hernandez D.G.
        • Greenway M.J.
        • Bradley D.G.
        • Traynor B.J.
        • Hardiman O.
        A genome-wide association study of sporadic ALS in a homogenous Irish population.
        Hum. Mol. Genet. 2008; 17: 768-774
        • Fogh I.
        • D'Alfonso S.
        • Gellera C.
        • Ratti A.
        • Cereda C.
        • Penco S.
        • Corrado L.
        • Sorarù G.
        • Castellotti B.
        • Tiloca C.
        • Gagliardi S.
        • Cozzi L.
        • Lupton M.K.
        • Ticozzi N.
        • Mazzini L.
        • Shaw C.E.
        • Al-Chalabi A.
        • Powell J.
        • Silani V.
        No association of DPP6 with amyotrophic lateral sclerosis in an Italian population.
        Neurobiol. Aging. 2011; 32: 966-967
        • Fransén E.
        • Tigerholm J.
        Role of A-type potassium currents in excitability, network synchronicity, and epilepsy.
        Hippocampus. 2010; 20: 877-887
        • Walz R.
        • Amaral O.B.
        • Rockenbach I.C.
        • Roesler R.
        • Izquierdo I.
        • Cavalheiro E.A.
        • Martins V.R.
        • Brentani R.R.
        Increased sensitivity to seizures in mice lacking cellular prion protein.
        Epilepsia. 1999; 40: 1679-1682
        • Rangel A.
        • Burgaya F.
        • Gavín R.
        • Soriano E.
        • Aguzzi A.
        • Del Río J.A.
        Enhanced susceptibility of Prnp-deficient mice to kainate-induced seizures, neuronal apoptosis, and death. Role of AMPA/kainate receptors.
        J. Neurosci. Res. 2007; 85: 2741-2755
        • Alier K.
        • Ma L.
        • Yang J.
        • Westaway D.
        • Jhamandas J.H.
        Aβ inhibition of ionic conductance in mouse basal forebrain neurons is dependent upon the cellular prion protein PrPC.
        J. Neurosci. 2011; 31: 16292-16297
        • Resenberger U.K.
        • Harmeier A.
        • Woerner A.C.
        • Goodman J.L.
        • Müller V.
        • Krishnan R.
        • Vabulas R.M.
        • Kretzschmar H.A.
        • Lindquist S.
        • Hartl F.U.
        • Multhaup G.
        • Winklhofer K.F.
        • Tatzelt J.
        The cellular prion protein mediates neurotoxic signalling of β-sheet-rich conformers independent of prion replication.
        EMBO J. 2011; 30: 2057-2070