Zn2+ interaction with Alzheimer amyloid beta protein calcium channels

The Alzheimer disease 40-residue amyloid beta protein (A beta P[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 A beta P[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 A beta P[1-40] channel. Provided the A beta P[1-40] channel is expressed in the low conductance (<400 pS) mode, Zn2+ blocks the open channel in a dose-dependent manner, For A beta P[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 A beta P[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 A beta P[1-40] channels indicating asymmetric Zn2+-A beta P[1-40] interactions at the entrance to the pore.