Internalization of transferrin (green)-bound receptor is blocked in cells lacking plasma membrane PIP2 (red cells).

Phosphoinositides (PIs) get the boot on page 377. Using a new method to eliminate PI(4,5)P2 from the plasma membrane, Varnai et al. create problems for receptor endocytosis and ion channels.

Until now, changing cellular PI levels in vivo meant playing the waiting game: express a kinase or phosphatase to make or eliminate a lipid species, and then wait half a day for the change to take place. During this lag, the gradual, persistent lipid modifications initiate trafficking and signaling events that distort the more immediate effect on any particular function.

Varnai and colleagues have now devised a quicker way to drop lipid levels. They hooked a drug-inducible plasma membrane targeting domain to a phosphatase that hydrolyzes PIP2. Add the drug, and voila: comparatively instant gratification that takes minutes at most.

The group used their method to prove a pair of suspected functions for PIP2. First, its loss from the plasma membrane blocked the internalization of growth factor receptors, presumably because the lipid is needed to recruit endocytic adaptor proteins.

Loss of PIP2 also prevented IP3-induced calcium waves and blocked activation of a cold-responsive ion channel. Whether the lipid is simply permissive for channel opening or regulates channel activity, perhaps by inducing conformational changes, is unresolved.

Having touched on the plasma membrane, the group now plans to tackle other cellular compartments and lipids. They are targeting the phosphatase to the Golgi, ER, and mitochondria, and looking into PI4P function, particularly during membrane trafficking.

Each new circumstance requires its own fine tuning, of course. Kinases and phosphatases might have their own targeting signals that must first be destroyed, and even cytoplasmic versions at high enough concentrations can change membrane lipid levels, the authors discovered. Yet their enthusiasm remains high, particularly as they get more and more PI levels to drop.