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Review
. 2020 Sep;22(3):207-222.
doi: 10.31887/DCNS.2020.22.3/blutz.

Neurobiology of cannabinoid receptor signaling

Beat Lutz  1
Affiliations
Review

Neurobiology of cannabinoid receptor signaling

Beat Lutz. Dialogues Clin Neurosci. 2020 Sep.

Abstract
in English, Spanish, French

The endocannabinoid system (ECS) is a highly versatile signaling system within the nervous system. Despite its widespread localization, its functions within the context of distinct neural processes are very well discernable and specific. This is remarkable, and the question remains as to how such specificity is achieved. One key player in the ECS is the cannabinoid type 1 receptor (CB1), a G protein-coupled receptor characterized by the complexity of its cell-specific expression, cellular and subcellular localization, and its adaptable regulation of intracellular signaling cascades. CB1 receptors are involved in different synaptic and cellular plasticity processes and in the brain's bioenergetics in a context-specific manner. CB2 receptors are also important in several processes in neurons, glial cells, and immune cells of the brain. As polymorphisms in ECS components, as well as external impacts such as stress and metabolic challenges, can both lead to dysregulated ECS activity and subsequently to possible neuropsychiatric disorders, pharmacological intervention targeting the ECS is a promising therapeutic approach. Understanding the neurobiology of cannabinoid receptor signaling in depth will aid optimal design of therapeutic interventions, minimizing unwanted side effects. .

El sistema endocannabinoide (SEC) apareció como un sistema de señalización muy versátil en el sistema nervioso. A pesar de su existencia amplia y ubicua, sus funciones están integradas en el contexto de distintos procesos neuronales y, en última instancia, son bastante bien discernibles y específicas. Esto es notable, y la pregunta sigue siendo ¿cómo puede surgir tal especificidad ? Un jugador clave del SEC es el receptor cannabinoide CB1; se trata de un receptor acoplado a proteína G, que se caracteriza por su complejidad de expresión específica del tipo celular, localización celular y subcelular y por su capacidad para la regulación adaptativa de las cascadas de señalización intracelular. El receptor CB1 participa en diferentes procesos de plasticidad sináptica y celular y en la bioenergética del cerebro de una manera contexto-específica. El receptor CB2 también se ha convertido en un actor importante en varios procesos en neuronas y células inmunes que residen en el cerebro. Las intervenciones farmacológicas dirigidas al SEC siguen siendo un enfoque terapéutico prometedor, dado que tanto los polimorfismos en los componentes del SEC, como los impactos externos (el estrés y las exigencias metabólicas) pueden conducir a una actividad desregulada del SEC y, posteriormente, a posibles trastornos neuropsiquiátricos. Una comprensión profunda de la neurobiología de la señalización de los receptores de cannabinoides ayudará a diseñar intervenciones terapéuticas de manera óptima, minimizando los efectos secundarios no deseados.

Le système endocannabinoïde (SEC) se comporte comme un système de signalisation très polyvalent au sein du système nerveux. Il est surprenant d’observer que ses fonctions, s'intégrant dans un cadre de processus neuronaux distincts, sont finalement très perceptibles et spécifiques malgré son étendue et son caractère ubiquitaire et l’on peut s’interroger sur l’origine d’une telle spécificité. Le récepteur cannabinoïde CB1, couplé à la protéine G, est au centre du SEC : il est caractérisé par sa complexité d'expression spécifique au type cellulaire, sa localisation cellulaire et sous-cellulaire et sa capacité de régulation flexible des cascades de signalisation intracellulaire. Le récepteur CB1 est impliqué dans différents processus de plasticité synaptique et cellulaire et il participe à la bioénergétique du cerveau selon le contexte. Le récepteur CB2 est également un acteur majeur dans plusieurs mécanismes neuronaux et des cellules immunitaires cérébrales. Le SEC pouvant être perturbé par des facteurs extérieurs comme le stress et les troubles métaboliques comme par ses composants polymorphes, générant par conséquent d'éventuels troubles neuropsychiatriques, les traitements médicamenteux le ciblant restent une approche thérapeutique prometteuse. Ces traitements seront d’autant plus efficaces et bien tolérés que nous comprendrons en détail la neurobiologie de la signalisation des récepteurs cannabinoïdes.

Keywords: 2-arachidonoylglycerol; anandamide; behavior; cannabinoid receptor; neural communication.

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Figures

Figure 1.
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.
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.
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
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