Upon ligand binding, GRs are desensitized and targeted for internalization through either a clathrin-mediated pathway or through caveolae. The internalization involves β-arrestins, which colocalize with the receptors at the membrane and intracellularly. The internalized receptors rapidly enter early endosomes. Second messengers GRK2, GRK3 and GRK5 as well as PKCα stimulate receptor internalization. Abbreviations: G, glucagon; GR, glucagon receptor; AR, β-arrestins; CCP, clathrin coated pit; CCV, clathrin-coated vesicle; EE, early endosome; CAV, caveolae; CS, caveosome; GRK, G protein-coupled receptor kinase; PAO, phenylarsine oxide; N, nucleus; DN, dominant negative.