amyloid-beta-peptides and rubidium-chloride

1. The lipid bilayer technique was used to characterize the biophysical and pharmacological properties of several ion channels formed by incorporating amyloid beta protein fragment (AbetaP) 1-40 into lipid membranes. Based on the conductance, kinetics, selectivity, and pharmacological properties, the following AbetaP[1-40]-formed ion channels have been identified: (i) The AbetaP[1-40]-formed "bursting" fast cation channel was characterized by (a) a single channel conductance of 63 pS (250/50 mM KCl cis/trans) at +140 mV. 17 pS (250/50 mM KCl cis/trans) at -160 mV, and the nonlinear current-voltage relationship drawn to a third-order polynomial, (b) selectivity sequence PK > PNa > PLi = 1.0:0.60:0.47, (c) Po of 0.22 at 0 mV and 0.55 at +120 mV, and (d) Zn2+-induced reduction in current amplitude, a typical property of a slow block mechanism. (ii) The AbetaP[1-40]-formed "spiky" fast cation channel was characterized by (a) a similar kinetics to the "bursting" fast channel with exception for the absence of the long intraburst closures, (b) single channel conductance of 63 pS (250/50 KCl) at +140 mV 17 pS (250/50 KCl) at -160 mV, the current-voltage relationship nonlinear drawn to a third-order polynomial fit, and (c) selectivity sequence PRb > (iii) The AbetaP[1-40]-formed medium conductance channel was charcterized by (a) 275 pS (250/50 mM KCl cis/trans) at +140 mV and 19 pS (250/50 mM KCl cis/trans) at -160 mV and (b) inactivation at Vms more negative than -120 and more positive than +120 mV. (iv) The AbetaP[1-40]-formed inactivating large conductance channel was characterized by (a) fast and slow modes of opening to seven multilevel conductances ranging between 0-589 pS (in 250/50 mM KCI) at +140 mV and 0-704 pS (in 250/50 mM KCl) at -160 mV. (b) The fast mode which had a conductance of <250 pS was voltage dependent. The inactivation was described by a bell-shaped curve with a peak lag time of 7.2 s at +36 mV. The slow mode which had a conductance of >250 pS was also voltage dependent. The inactivation was described by a bell-shaped curve with a peak lag time of 7.0 s at -76 mV, (c) the value of PK/Pcholine for the fast mode was 3.9 and selectivity sequence PK > PCs > PNa > PLi = 1.0:0.94:0.87:0.59. The value of PK/Pcholine for the slow mode was 2.7 and selectivity sequence PK > FNa > PLi > PCs = 1.0:0.59:0.49:0.21, and (d) asymmetric blockade with 10 mM Zn2+-induced reduction in the large conductance state of the slow mode mediated via slow block mechani

Topics: Alzheimer Disease; Amyloid beta-Peptides; Cations; Cesium; Chlorides; Humans; Ion Channel Gating; Ion Channels; Kinetics; Lipid Bilayers; Lithium Chloride; Membrane Potentials; Patch-Clamp Techniques; Peptide Fragments; Potassium Chloride; Rubidium; Signal Transduction; Sodium Chloride; Structure-Activity Relationship; Zinc Compounds