Cholesterol and Ion Channels

Abstract

A variety of ion channels, including members of all major ion channel families, have been shown to be regulated by changes in the level of membrane cholesterol and partition into cholesterol-rich membrane domains. In general, several types of cholesterol effects have been described. The most common effect is suppression of channel activity by an increase in membrane cholesterol, an effect that was described for several types of inwardly-rectifying K(+) channels, voltage-gated K(+) channels, Ca(+2) sensitive K(+) channels, voltage-gated Na(+) channels, N-type voltage-gated Ca(+2) channels and volume-regulated anion channels. In contrast, several types of ion channels, such as epithelial amiloride-sensitive Na(+) channels and Transient Receptor Potential channels, as well as some of the types of inwardly-rectifying and voltage-gated K(+) channels were shown to be inhibited by cholesterol depletion. Cholesterol was also shown to alter the kinetic properties and current-voltage dependence of several voltage-gated channels. Finally, maintaining membrane cholesterol level is required for coupling ion channels to signalling cascades. In terms of the mechanisms, three general mechanisms have been proposed: (i) specific interactions between cholesterol and the channel protein, (ii) changes in the physical properties of the membrane bilayer and (iii) maintaining the scaffolds for protein-protein interactions. The goal of this review is to describe systematically the role of cholesterol in regulation of the major types of ion channels and to discuss these effects in the context of the models proposed.