From Crosstalk to Synergism: The Combined Effect of Cholesterol and PI(4,5)P₂ on Inwardly Rectifying Potassium Channels

Inwardly rectifying potassium (Kir) channels are integral membrane proteins that control the flux of potassium ions across cell membranes and regulate membrane permeability. All eukaryotic Kir channels require the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P₂) for activation. In recent years, it has become evident that the function of many members of this family of channels is also mediated by another essential lipid—cholesterol. Here, we focus on members of the Kir2 and Kir3 subfamilies and their modulation by these two key lipids. We discuss how PI(4,5)P₂ and cholesterol bind to Kir2 and Kir3 channels and how they affect channel activity. We also discuss the accumulating evidence indicating that there is interplay between PI(4,5)P₂ and cholesterol in the modulation of Kir2 and Kir3 channels. In particular, we review the crosstalk between PI(4,5)P₂ and cholesterol in the modulation of the ubiquitously expressed Kir2.1 channel and the synergy between these two lipids in the modulation of the Kir3.4 channel, which is primarily expressed in the heart. Additionally, we demonstrate that there is also synergy in the modulation of Kir3.2 channels, which are expressed in the brain. These observations suggest that alterations in the relative levels PI(4,5)P₂ and cholesterol may fine-tune Kir channel activity.