Lipids diffuse in a cell membrane at least fivefold more slowly than they do in an artificial lipid bilayer, a discrepancy that has puzzled cell biologists for more than two decades. Now, on page 1071, Fujiwara et al. suggest an explanation: the cell surface is crisscrossed with picket fences made of immobile transmembrane proteins.

Until now, single-particle tracking (SPT) has been too slow to provide a high-resolution view of lipid diffusion. In an impressive technical achievement, the authors developed a SPT technique with 25-μs resolution, and then used it to follow the diffusion of a nonraft lipid in a cell membrane.

The lipid molecule was confined within a defined compartment for an average of 11 ms before hopping to an adjacent compartment on the cell membrane. Within the compartment, diffusion was about as fast as in artificial membranes, but movement from one compartment to another took much longer. The long-range diffusion rate of the lipid was determined primarily by the rate of hopping between compartments.

Surprisingly, compartmentalization of the membrane did not depend on the extracellular matrix, lipid rafts, or the extracellular domains of membrane proteins. Instead, the actin-based membrane cytoskeleton, located on the cytoplasmic face of the membrane, is responsible for confining diffusion on the extracellular face of the membrane. The authors propose that various transmembrane proteins interacting with the cytoskeleton act as rows of pickets, temporarily confining phospholipids to particular membrane domains.

Preliminary studies have now shown that raft lipids display hop diffusion rates similar to those of nonraft lipids, suggesting that rafts may continually form and disperse, rather than remaining intact as large structures. Because picket barriers would affect all membrane molecules, compartmentalization should also limit the movement of transmembrane and GPI-anchored proteins, possibly helping confine signaling complexes in compartments where extracellular signals are received. ▪