We investigated the action of the acridine derivative, quinacrine (QC), which has been shown to act as a noncompetitive channel inhibitor. The main effects of QC are voltage- and concentration-dependent changes in the kinetics of the prion protein fragment (PrP[106-126])-formed cation channels. The current-voltage relationships show that the maximal current (I) was not affected whereas the physiologically important mean current (I') was reduced as a result of changes in channel kinetics. These findings suggest that QC acts on the open state of the channels. The half-inhibitory concentration (IC50) for the dose-dependent effects of [QC]cis on the kinetic parameters of the PrP(106-126)-formed cation channel shows a reduction in the ratios Po(QC)/Po, Fo(QC)/Fo, and To(QC)/To, whereas Tc(QC)/Tc increases. Of these ratios, Po(QC)/Po was more sensitive than the others. The corresponding IC50 for these ratios were 51, 94, 86, and 250 microM QC, respectively. The QC-induced changes in the kinetic parameters were more apparent at positive voltages. IC50 values for Po were 95, 75, and 51 microM at +20, +80, and +140 mV, respectively. The fact that QC induced changes in the kinetics of this channel, although the conductance of the channel remained unchanged, indicates that QC may bind at the mouth of the channel via a mechanism known as fast channel block. The QC-induced changes in the kinetic parameters of this channel suggest that they are pathophysiologically significant because these channels could be the mechanisms by which amyloids induce membrane damage in vivo.
Copyright 2003 Wiley-Liss, Inc.