Physiological roles and cholesterol sensitivity of endothelial inwardly-rectifying K⁺ channels: Specific cholesterol-protein interactions through non annular binding sites

Inwardly-rectifying K ⁺ channels (Kir) have been implicated to play a major role in endothelial sensation of shear stress forces and suggested to constitute a primary fl ow sensor. The studies of our group focused on elucidating the impact of hypercholesterolemia on endothelial Kir channels and elucidating molecular, biophysical and structural basis of cholesterol-induced Kir suppression. In this chapter, we fi rst review briefl y what is known about expression of Kir channels in different types of endothelial cells and their role in endothelial function and then discuss in detail the mechanisms of cholesterol-Kir interactions. Briefl y, endothelial Kir channels are suppressed by loading the cells with cholesterol and by exposing them to atherogenic lipoproteins in vitro and by plasma hypercholesterolemia in vivo. A series of studies revealed that cholesterol interacts with the channels directly stabilizing them in a long-lived closed “silent” state and that multiple structural features of the channels are essential for conferring their cholesterol sensitivity. There is also a signifi cant cross-talk between cholesterol, caveolin-1 and a regulatory phospholipid PI(4,5)P ₂in the regulation of these channels. Further studies are needed to determine the impact of cholesterol-induced suppression of Kir on endothelial function.