Allosteric Modulation of GPCRs of Class A by Cholesterol

G-protein coupled receptors (GPCRs) are membrane proteins that convey extracellular signals to the cellular milieu. They represent a target for more than 30% of currently marketed drugs. Here we review the effects of membrane cholesterol on the function of GPCRs of Class A. We review both the specific effects of cholesterol mediated via its direct high-affinity binding to the receptor and non-specific effects mediated by cholesterol-induced changes in the properties of the membrane. Cholesterol binds to many GPCRs at both canonical and non-canonical binding sites. It allosterically affects ligand binding to and activation of GPCRs. Additionally, it changes the oligomerization state of GPCRs. In this review, we consider a perspective of the potential for the development of new therapies that are targeted at manipulating the level of membrane cholesterol or modulating cholesterol binding sites on to GPCRs.

Automated summary

G-protein coupled receptors (GPCRs) are membrane proteins that transmit extracellular signals to cells, and membrane cholesterol plays a significant role in regulating their function through direct binding and membrane property changes. Cholesterol affects ligand binding and activation of GPCRs, as well as altering their oligomerization state. Manipulating membrane cholesterol levels or modulating cholesterol binding sites on GPCRs may have potential for the development of new therapies.