Uncovering the intimate relationship between lipids, cholesterol and GPCR activation

The membrane bilayer has a significant influence over the proteins embedded within it. G protein-coupled receptors (GPCRs) form a large group of membrane proteins with a vast array of critical functions, and direct and indirect interactions with the bilayer are thought to control various essential aspects of receptor function. The presence of cholesterol, in particular, has been the focus of a number of recent studies, with varying receptor-dependent effects reported. However, the possibility of specific cholesterol binding sites on GPCRs remains debatable at present. A deeper structural and mechanistic understanding of the complex and delicately balanced nature of GPCR–bilayer interactions has only been revealed so far in studies with the non-ligand binding, class A GPCR, rhodopsin. Further investigations are essential if we are to appreciate fully the role of the bilayer composition in GPCR activation and signalling; indeed, recent improvements in GPCR expression and purification, along with development of novel reconstitution methods should make these types of biophysical investigations much more accessible. In this review we highlight the latest research on GPCR–membrane interactions and some of the tools available for more detailed studies.

► GPCRs in vivo.
► Influence of the bilayer on rhodopsin activation.
► The role of cholesterol in GPCR activity.
► Technical challenges for the study of lipid GPCR interaction.