Cu2+-induced modification of the kinetics of A beta(1-42) channels.
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.
Bahadi
Randa
R
Membrane Transport Group, Department of Chemistry, The Faculties, The Australian National University, Canberra, Australian Capital Territory 0200, Australia.
Farrelly
Peter V
PV
Kenna
Bronwyn L
BL
Curtain
Cyril C
CC
Masters
Colin L
CL
Cappai
Roberto
R
Barnham
Kevin J
KJ
Kourie
Joseph I
JI
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*
D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D007473:Ion Channels; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D003300:Copper; D007464:Clioquinol