Structural Determinants of the Regulation of Kir Channels by Cholesterol

Abstract

A variety of ion channels are regulated by cholesterol, a major lipid component of the plasma membrane whose excess is associated with multiple pathological conditions. However, the mechanism underlying cholesterol sensitivity of ion channels is unknown. We have recently shown that an increase in membrane cholesterol strongly suppresses inwardly rectifying Kir2 channels. Here we show that cholesterol sensitivity of Kir2 channels depends on a specific region of the C-terminus of the cytosolic domain of the channel, the CD loop. Furthermore, we also show that KirBac1.1, a bacterial homologue of mammalian Kir channels, is also suppressed by the elevation membrane cholesterol when incorporated into liposomes. These findings suggest that Kir channels are directly regulated by membrane cholesterol and provide first insights into the structural determinants of the sensitivity of Kir2 channels to cholesterol introducing the critical role of the cytosolic domain in cholesterol dependent channel regulation.