Zn2+ interaction with Alzheimer amyloid beta protein calcium channels.
The Alzheimer disease 40-residue amyloid beta protein (AbetaP[1-40]) forms cation-selective channels across acidic phospholipid bilayer membranes with spontaneous transitions over a wide range of conductances ranging from 40 to 4000 pS. Zn2+ has been reported to bind to AbetaP[1-40] with high affinity, and it has been implicated in the formation of amyloid plaques. We now report the functional consequences of such Zn2+ binding for the AbetaP[1-40] channel. Provided the AbetaP[1-40] channel is expressed in the low conductance (<400 pS) mode, Zn2+ blocks the open channel in a dose- dependent manner. For AbetaP[1-40] channels in the giant conductance mode (>400 pS), Zn2+ doses in the millimolar range were required to exert substantial blockade. The Zn2+ chelator o-phenanthroline reverses the blockade. We also found that Zn2+ modulates AbetaP[1-40] channel gating and conductance only from one side of the channel. These data are consistent with predictions of our recent molecular modeling studies on AbetaP[1-40] channels indicating asymmetric Zn(2+)-AbetaP[1-40] interactions at the entrance to the pore.
Arispe
N
N
Laboratory of Cell Biology and Genetics, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Pollard
H B
HB
Rojas
E
E
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000378:metabolism* / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D046911:Macromolecular Substances; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D010618:Phenanthrolines / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D046911:Macromolecular Substances; D010446:Peptide Fragments; D010618:Phenanthrolines; C078592:amyloid beta-protein (1-40); D015032:Zinc; C025205:1,10-phenanthroline