Zn²⁺ interaction with Alzheimer amyloid β protein calcium channels

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