ZN2-BETA PROTEIN CALCIUM CHANNELS( INTERACTION WITH ALZHEIMER AMYLOID)

The Alzheimer disease 40-residue amyloid beta protein (A beta P[1-40]) forms cation-selective channels across acidic phospholipid bilayer me mbranes 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 formatio n of amyloid plaques, We now report the functional consequences of suc h 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, Zn2blocks 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 m illimolar range were required to exert substantial blockade. The Zn2chelator o-phenanthroline reverses the blockade. We also found that Zn 2+ modulates A beta P[1-40] channel gating and conductance only from o ne side of the channel, These data are consistent with predictions of our recent molecular modeling studies on A beta P[1-40] channels indic ating asymmetric Zn2+-A beta P[1-40] interactions at the entrance to t he pore.