title: Amyloid beta peptide as a physiological modulator of neuronal 'A'-type K+ current.
abstract: Control of neuronal spiking patterns resides, in part, in the type and degree of expression of voltage-gated K(+) channel subunits. Previous studies have revealed that soluble forms of the Alzheimer's disease associated amyloid beta protein (Abeta) can increase the 'A'-type current in neurones. In this study, we define the molecular basis for this increase and show that endogenous production of Abeta is important in the modulation of Kv4.2 and Kv4.3 subunit expression in central neurones. A-type K(+) currents, and Kv4.2 and Kv4.3 subunit expression, were transiently increased in cerebellar granule neurones by the 1-40 and 1-42 forms of Abeta (100nM, 2-24h). Currents through recombinant Kv4.2 channels expressed in HEK293 cells were increased in a similar fashion to those through the native channels. Increases in 'A'-type current could be prevented by the use of cycloheximide and brefeldin A, indicating that protein expression and trafficking processes were altered by Abeta, rather than protein degredation. Endogenous Abeta production in cerebellar granule neurones was blocked using inhibitors of either gamma- or beta-secretase and resulted in decreased K(+) current. Crucially this could be prevented by co-application of exogenous Abeta (1nM), however, no change in Kv4.2 or Kv4.3 subunit expression occurred. These data show that Abeta is a modulator of Kv4 subunit expression in neurones at both the functional and the molecular level. Thus Abeta is not only involved in Alzheimer pathology, but is also an important physiological regulator of ion channel expression and hence neuronal excitability.
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Leigh D
authors.initials: LD
authors.lastname: Plant
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Webster
authors.forename: John P
authors.initials: JP
authors.lastname: Boyle
authors.forename: Martin
authors.initials: M
authors.lastname: Ramsden
authors.forename: Darragh B
authors.initials: DB
authors.lastname: Freir
authors.forename: Chris
authors.initials: C
authors.lastname: Peers
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Pearson
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D015153:Blotting, Western; D020126:Brefeldin A / Q000494:pharmacology; D018929:Cell Culture Techniques; D002460:Cell Line; D002531:Cerebellum / Q000166:cytology; D003513:Cycloheximide / Q000494:pharmacology; D004594:Electrophysiology; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D051672:Shal Potassium Channels / Q000378:metabolism*; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D024642:Potassium Channels, Voltage-Gated; D051672:Shal Potassium Channels; C078592:amyloid beta-protein (1-40); D020126:Brefeldin A; D003513:Cycloheximide; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human