How Highly Charged Anionic Lipids Bind and Regulate Ion Channels

The modulation of channel activity by direct interaction with membrane lipids is now an emerging theme in ion channel biology. In particular, phosphoinositides such as phosphatidylinositol 4,5-bisphosphate (PIP 2 ) are known to regulate the activity of most major classes of ion channel, as well as a number of other membrane transport proteins. The regulation of inwardly rectifying (Kir) potassium channels by PIP 2 is one of the most intensively studied and best-defi ned model systems for studying channel -lipid interactions. In this review we explore the mechanisms that underlie the complex regulation of Kir channels by phosphoinositides and other highly charged anionic lipids such as long chain CoA esters. Intriguingly, these different lipids result in either activation or inhibition depending on the Kir channel subtype. We describe how recent studies have provided structural insight into these lipid-induced gating movements, and discuss how this gating mechanism is central to Kir channel physiology.