Cu2+-induced modification of the kinetics of A{beta}(1-42) channels

1 Membrane Transport Group, Department of Chemistry, The Faculties, The Australian National University, Canberra, Australian Capital Territory 0200; 2 Department of Pathology, The University of Melbourne, Victoria 3010; and 3 The Mental Health Research Institute, Parkville, Victoria 3052, Australia Submitted 14 April 2003 ; accepted in final form 21 May 2003 We found that the amyloid peptide A (1-42) is capable of interacting with membrane and forming heterogeneous ion channels in the absence of any added Cu 2+ or biological redox agents that have been reported to mediate A (1-42) toxicity. The A (1-42)-formed cation channel was inhibited by Cu 2+ in cis solution ([Cu 2+ ] cis ) in a voltage- and concentration-dependent manner between 0 and 250 µM. The [Cu 2+ ] cis -induced channel inhibition is fully reversible at low concentrations between 50 and 100 µM [Cu 2+ ] cis and partially reversible at 250 µM [Cu 2+ ] cis . The inhibitory effects of [Cu 2+ ] cis between 50 and 250 µM on the channel could not be reversed with addition of Cu 2+ -chelating agent clioquinol (CQ) at concentrations between 64 and 384 µM applied to the cis chamber. The effects of 200-250 µM [Cu 2+ ] 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 Cu 2+ -induced inhibition was mediated via both desensitization and an open channel block mechanism and that Cu 2+ binds to the histidine residues located at the mouth of the channel. It is proposed that the Cu 2+ -binding site of the A (1-42)-formed channels is modulated with Cu 2+ in a similar way to those of channels formed with the prion protein fragment PrP(106-126), suggesting a possible common mechanism for Cu 2+ modulation of A and PrP channel proteins linked to neurodegenerative diseases. neurodegenerative diseases; transitional metals; ion channel pathologies; membrane injuries; calcium homeostasis Address for reprint requests and other correspondence: J. I. Kourie, Membrane Transport Group, Dept. of Chemistry, The Faculties, Science Road Bldg. 33, The Australian National Univ., Canberra, Australian Capital Territory 0200, Australia (E-mail: joseph.kourie{at}anu.edu.au ).