Cell signaling of the CB1 cannabinoid receptor via β-arrestins, cannabinoid receptor interacting protein (CRIP1a) and other regulatory proteins

The CB1 cannabinoid receptor (CB1R) is associated with proteins that regulate cellular signaling responses to endocannabinoids 2-arachidoylglycerol and anandamide, the phytocannabinoid Δ9-tetrahydrocannabinol, and other agonists (CP55940, WIN55212-2).  CB1Rs activate heterotrimeric G proteins (predominantly Gi/o), allowing Giα-GTP and G βγ to direct initial cellular signaling. Regulators of G protein signaling (RGS) proteins facilitate inactivation of Gαi by hydrolysis of GTP to GDP. G protein-coupled receptor kinases phosphorylate CB1Rs. This promotes binding of β-arrestins1 and 2, which scaffold to alternative cellular signaling proteins or clathrin for internalization. Cannabinoid Receptor Interacting Protein1a (CRIP1a) binds Gαi and attenuates signaling, and competes with β-arrestins1 and 2 for the CB1R. Proteins that regulate CB1R intracellular trafficking include: Binding Protein (BiP), SH3 domain GRB2-like (endothelin) interacting protein1 (SGIP1), Wntless/GPR177 (WLS) and G protein-coupled receptor-associated sorting protein1 (GASP1).  Failure of these associated proteins to function in signal transduction or the CB1R life cycle contributes to disease states.