Cannabinoid receptor type-1: breaking the dogmas

Abstract

The endocannabinoid system (ECS) is abundantly expressed in the brain. This system regulates a plethora of physiological functions and is composed of cannabinoid receptors, their endogenous ligands (endocannabinoids), and the enzymes involved in the metabolism of endocannabinoids. In this review, we highlight the new advances in cannabinoid signaling, focusing on a key component of the ECS, the type-1 cannabinoid receptor (CB 1). In recent years, the development of new imaging and molecular tools has demonstrated that this receptor can be distributed in many cell types (e.g., neuronal or glial cells) and intracellular compartments (e.g., mitochondria). Interestingly, cellular and molecular effects are differentially mediated by CB 1 receptors according to their specific localization (e.g., glutamatergic or GABAergic neurons). Moreover, this receptor is expressed in the periphery, where it can modulate periphery-brain connections. Finally, the better understanding of the CB 1 receptor structure led researchers to propose interesting and new allosteric modulators. Thus, the advances and the new directions of the CB 1 receptor field will provide new insights and better approaches to profit from its interesting therapeutic profile.

Keywords: CB1 receptor signaling; Endocannabinoid system; allosteric modulator; cannabinoid ligands; molecular pharmacology.

Figure 1.. Schematic comparison between the classic and the current view of the CB ₁ receptor functional expression.

On the left panel, the classic view of the CB ₁ receptor is represented. The CB ₁ receptor was thought to be exclusively localized in GABAergic neurons, where it was demonstrated to inhibit neurotransmitter release. On the right panel, the current view of the CB ₁ receptor is illustrated. Different advances have completely changed this picture: ( A) The CB ₁ receptor is present in different neuronal types and in glial cells, both in astrocytes ( B) and potentially in microglia ( C). Furthermore, it is found intracellularly in the mitochondria ( D) and endosomes ( E). The view of a canonical retrograde system changed after the CB ₁ receptor localization in postsynaptic somatodentritic neurons was demonstrated ( F). Nowadays, we know that CB ₁ receptor presents allosteric binding sites ( G) and that it could form heteromers ( H). Beyond the brain, the CB ₁ receptor is widely expressed in the periphery ( I), where it can modulate the periphery-brain connection. All of this new knowledge reflects the complexity of the central nervous system and the advance in neuroscience, positing the CB ₁ receptor as an ideal tool for studying brain functions. CB ₁, cannabinoid receptor-1; CB ₂, cannabinoid receptor-2; eCB, endocannabinoid; NT, neurotransmitter.