Cannabinoid receptor (CB)

Cannabinoid receptors are part of the endocannabinoid system and function as G protein-coupled receptors with seven transmembrane spanning domains. There are two main subtypes: CB1 and CB2. CB1 is predominantly expressed in the brain and central nervous system, but also found in peripheral tissues including lungs, liver, kidneys, and skeletal muscle. CB2 is mainly expressed in immune cells and hematopoietic cells, with some expression in the brain. The protein sequences of CB1 and CB2 receptors share about 44% similarity overall, with approximately 68% similarity in their transmembrane regions. These receptors are activated by three major groups of ligands: endocannabinoids (naturally produced in the body), phytocannabinoids (plant-derived compounds like THC from cannabis), and synthetic cannabinoids. All endocannabinoids and phytocannabinoids are lipophilic in nature. CB1 receptors mediate the psychoactive effects of THC and modulate neurotransmitter release at presynaptic neurons. The receptor structure includes an extracellular N-terminal domain, seven transmembrane spanning alpha helices, three extracellular loops, three intracellular loops, and an intracellular G protein binding domain. Several proteins interact with cannabinoid receptors to regulate their function, including CRIP1a (Cannabinoid Receptor Interacting Protein 1a), β-arrestin, AP-3, GASP1, and FAN (Factor Associated with Neutral sphingomyelinase). These interacting proteins contribute to the diverse cellular signaling pathways and suggest potential for developing agonists and allosteric modulators that could specifically regulate unique, cell type-specific responses.

Other names

CB1 (Cannabinoid receptor 1)CB2 (Cannabinoid receptor 2)CNR1 (gene symbol for CB1)CNR2 (gene symbol for CB2)hCB1a (human CB1 splice variant)hCB1b (human CB1 splice variant)

G-protein signaling (primarily inhibitory Gi/o), Inhibition of calcium channels, Modulation of MAPK pathways, Activation of JNK signaling, Regulation of cAMP levels, ERK phosphorylation, Ceramide signaling via FAN. Upon activation, GTP is exchanged for GDP at the G protein α subunit, leading to its dissociation from the βγ subunits and initiating downstream signaling cascades.