State-Dependence of Ion and ATP Transport in VDAC1 Protein Investigated with GCMC/BD Simulations

Abstract

Long QT shown to affect channel interactions with phospholipids, increase sensitivity to PKCbII-mediated internalization, leading to decrease in membrane expression that can be rescued by PKCbII inhibition. We show that reduction of PI4P and not PIP 2 levels reduce channel membrane localization in a PKCbII-dependent manner. Finally, we show that patients carrying mutations in putative phospholipid-interacting sites are at higher risk for cardiac arrhythmias. Our data suggest that PKCbII-PI4P signaling leads to channel internalization that has a major role on QT prolongation in inherited and acquired Long QT syndrome.