Neurobiology of cannabinoid receptor signaling


Figures & data

Figure 1. Expression of cannabinoid type 1 and type 2 (CB₁ and CB₂) receptors in neural tissue. The endocannabinoid system is present in neurons, astrocytes, oligodendrocytes, oligodendrocyte precursor cells (OPCs), and microglia. Functional CB₁ receptors are located on the plasma membrane, but also in mitochondria (mtCB₁) of neurons and astrocytes. Presynaptic CB₁ receptor suppresses neurotransmitter release, as shown here, at a glutamatergic synapse. For this process, postsynaptic increase of Ca²⁺ triggers the synthesis of endocannabinoids, which travel to the presynapse to activate CB₁ receptor. Astrocytic CB₁ receptor can regulate gliotransmitter release. AMPAR, AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) type glutamate receptor; CB₁/CB₂, cannabinoid type 1/type 2 receptor; eCB, endocannabinoid; mGluR5, metabotropic glutamate receptor 5; mtCB₁, mitochondrial CB₁ receptor; NMDAR, NMDA (N-methyl-D-aspartate receptor) type glutamate receptor; OPC, oligodendrocyte precursor cell; TRPV1, transient receptor potential cation channel subfamily V member 1

Figure 2. Neurogenesis in the subgranular zone of the adult brain hippocampus. Both cannabinoid type 1 and type 2 (CB₁ and CB₂) receptors are expressed in neural stem cells and neural progenitor cells and participate in the proliferation of neural stem cells. CB1 receptor also acts later on in the differentiation of the newly generated neurons with regard to dendritic length and spine number. CB₁/CB₂, cannabinoid type 1/type 2 receptor

Figure 3. The endocannabinoid system is a homeostatic system. (A) It is proposed that various physiological processes need optimal ECS activity to maintain a homeostatic set-point. Aberrant ECS activity may lead to allostatic set-points, with the emergence of various diseases. (B) The shift from a homeostatic to an allostatic set-point may have different origins, such as genetic causes, but also life events and life history (eg, stress, trauma, metabolic challenges), acting, among others, via epigenetic mechanisms. (C) Pharmacological interventions aiming at regaining homeostasis by targeting different ECS components using different mechanistic approaches. (D) Pharmacological interventions targeting the different ECS components. Compounds acting on cannabinoid receptors with biased signaling effects toward G protein or β–arrestin pathways contain high potentials. 2-AG, 2-arachidonoylglycerol; AEA, anandamide (arachidonoylethanolamide); CB₁/CB₂, cannabinoid type 1/type 2 receptor; DAGL, diacylglycerol lipase; eCB, endocannabinoid; ET, eCB transporter; FAAH, fatty acid amide hydrolase; MAGL, monoacylglycerol lipase; NAM, negative allosteric receptor modulator; NAPE-PLD, 2-acyl phosphatidylethanolamide-specific phospholipase D; PAM, positive allosteric receptor modulator; PTSD, posttraumatic stress disorder