Schematic of G protein-coupled receptor post-translational modifications and interactions. GPCRs have seven transmembrane domains (TMs) with an extracellular amino terminus and intracellular carboxyl terminus and alternating intracellular and extracellular loops. They undergo a variety of post-translational modifications and interact with various components of the membrane. (1) The amino terminus and extracellular loops of receptors are often glycosylated, which can be vital for correct cell-surface localization. (2) The carboxy-terminal tail undergoes reversible phosphorylation, which is important in signal desensitization and receptor internalization. (3) Reversible palmitoylation of cysteine residues within intracellular loops and the carboxy-terminal tail results in different loop conformations as the palmitate groups penetrate into the lipid bilayer. (4) Cholesterol can interact at specific sites within the TM helices of GPCRs, in this case TM2 and TM4. (5) GPCRs also may also interact with specific lipid components of the membrane. These interactions and modifications act in concert to modulate the activity of GPCRs.