Figure 3.

Regulation of KCC2 membrane trafficking by lateral diffusion, clustering and endocytosis. Different subpopulations of KCC2 exist in the plasma membrane: freely moving KCC2 outside of clusters and confined KCC2 in membrane clusters. KCC2 clustering probably results from its accumulation in lipid-rafts, interaction with the cytoskeleton via protein 4.1N and oligomerization of the transporter. Freely moving molecules are more susceptible to interact with molecules involved in clathrin-dependent endocytosis such as AP-2. Confinement of KCC2 in membrane clusters may therefore prevent transporter endocytosis, a mechanism favoring chloride extrusion. The balance between “freely moving” and “clustered” pools of KCC2 can be rapidly changed by activity through phosphoregulations, which regulate the overall density of transporters localized at the membrane.