Figure 5. CB₁R desensitization.

Upon activation of CB₁R by an agonist (A), the coupled G protein disassociates. While the alpha subunit participates in signaling mechanisms, the beta and gamma complex recruits GRK. Phosphorylation of the C-terminus of CB₁R by GRK results in the recruitment of β–arrestin2 (βArr2) which causes steric inhibition and prevents the G protein from interacting with CB₁R. The association of β–arrestin2 with CB₁R also causes recruitment of adaptor protein-2 (AP-2) and clathrin which facilitate endocytosis of the receptor. This mechanism of desensitization reduces response to CB₁R activation and signaling, and repetitions of this process leads to downregulation and tolerance.