title: Cu2+-induced modification of the kinetics of A beta(1-42) channels.
abstract: We found that the amyloid beta peptide A beta(1-42) is capable of interacting with membrane and forming heterogeneous ion channels in the absence of any added Cu2+ or biological redox agents that have been reported to mediate A beta(1-42) toxicity. The A beta(1-42)-formed cation channel was inhibited by Cu2+ in cis solution ([Cu2+]cis) in a voltage- and concentration-dependent manner between 0 and 250 microM. The [Cu2+]cis-induced channel inhibition is fully reversible at low concentrations between 50 and 100 microM [Cu2+]cis and partially reversible at 250 microM [Cu2+]cis. The inhibitory effects of [Cu2+]cis between 50 and 250 microM on the channel could not be reversed with addition of Cu2+-chelating agent clioquinol (CQ) at concentrations between 64 and 384 microM applied to the cis chamber. The effects of 200-250 microM [Cu2+]cis on the burst and intraburst kinetic parameters were not fully reversible with either wash or 128 microM [CQ]cis. The kinetic analysis of the data indicate that Cu2+-induced inhibition was mediated via both desensitization and an open channel block mechanism and that Cu2+ binds to the histidine residues located at the mouth of the channel. It is proposed that the Cu2+-binding site of the A beta(1-42)-formed channels is modulated with Cu2+ in a similar way to those of channels formed with the prion protein fragment PrP(106-126), suggesting a possible common mechanism for Cu2+ modulation of A beta and PrP channel proteins linked to neurodegenerative diseases.
authors.affiliation: Membrane Transport Group, Department of Chemistry, The Faculties, The Australian National University, Canberra, Australian Capital Territory 0200, Australia.
authors.forename: Randa
authors.initials: R
authors.lastname: Bahadi
authors.forename: Peter V
authors.initials: PV
authors.lastname: Farrelly
authors.forename: Bronwyn L
authors.initials: BL
authors.lastname: Kenna
authors.forename: Cyril C
authors.initials: CC
authors.lastname: Curtain
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Roberto
authors.initials: R
authors.lastname: Cappai
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Kourie
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D007464:Clioquinol / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology*; D004553:Electric Conductivity; D004594:Electrophysiology; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D007700:Kinetics; D010446:Peptide Fragments / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D007473:Ion Channels; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D003300:Copper; D007464:Clioquinol