Lysophosphatidic acid (LPA) evokes growth-factor-like responses in many cells through three related LPA receptors. Like many receptors, these can be internalized by endocytosis but the full details of their regulation are unclear. Harish Radhakrishna and colleagues now shed light on key aspects of this, in particular the involvement of cholesterol (see ). The authors show that both clathrin and the adaptor protein β-arrestin are required for endocytosis of the LPA1 receptor and that β-arrestin, which targets many receptors to clathrin-coated pits, attenuates LPA signaling. In addition, they demonstrate that depletion of membrane cholesterol in HeLa cells inhibits LPA signalling, recruitment of β-arrestin to the membrane, and the subsequent endocytosis of LPA1. Finally, they show that LPA1 localizes to cholesterol-rich microdomains upon ligand stimulation. These results provide new insights into the link between clathrin-mediated endocytic events and cholesterol-dependent processes at the plasma membrane. They also reveal an important aspect of the regulation of LPA1, namely that cholesterol is required for its association with β-arrestin prior to its clathrin-dependent endocytosis.
