Cu2+-induced modification of the kinetics of Aβ(1-42) channels
We found that the amyloid β peptide Aβ(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 Aβ(1-42) toxicity. The Aβ(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 μM. The [Cu2+] cis-induced channel inhibition is fully reversible at low concentrations between 50 and 100 μM [Cu2+] cis and partially reversible at 250 μM [Cu2+] cis. The inhibitory effects of [Cu2+] cis between 50 and 250 μM on the channel could not be reversed with addition of Cu2+-chelating agent clioquinol (CQ) at concentrations between 64 and 384 μM applied to the cis chamber. The effects of 200-250 μM [Cu2+] cis on the burst and intraburst kinetic parameters were not fully reversible with either wash or 128 μM [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 Aβ(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 Aβ and PrP channel proteins linked to neurodegenerative diseases.