Abstract
The cannabinoid receptor type 1 (CB1R), a G protein-coupled receptor (GPCR), plays an essential role in the control of many physiological processes such as hunger, memory loss, gastrointestinal activity, catalepsy, fear, depression, and chronic pain. Therefore, it is an attractive target for drug discovery to manage pain, neurodegenerative disorders, obesity, and substance abuse. However, the psychoactive adverse effects, generated by CB1R activation in the brain, limit the use of the orthosteric CB1R ligands as drugs. The discovery of CB1R allosteric modulators during the last decade provided new tools to target the CB1R. Moreover, application of the site-directed mutagenesis in combination with advanced physical methods, especially X-ray crystallography and computational modeling, has opened new horizons for understanding the complexity of the structure, function, and activity of cannabinoid receptors. In this paper, we present the latest advances in research on the CB1R, its allosteric modulation and allosteric ligands, and their translational potential. We focused on structural essentials of the cannabinoid 1 receptor- ligand (drug) interactions, as well as modes of CB1R signaling regulation.
Highlights
G protein-coupled receptors (GPCRs) are integral membrane glycoproteins representing the largest family of cell-surface receptors, characterized by a presence of the seven-α-helical- transmembrane spanning (7TM) structural motif
We aimed to emphasize the important role of the extracellular loop ECL2 as one of the critical elements of the puzzle consisting of the cannabinoid receptor 1-ligand interactions, as well as modes of CB1R signaling regulation
CB1R can transduce signaling by non-G proteins pathways including the β-arrestins, the adaptor protein AP-3, GPCR-associated sorting proteins (GASP), the factor associated with neutral sphingomyelinase (FAN), and the cannabinoid receptor-interacting protein 1a (CRIP1a)
Summary
G protein-coupled receptors (GPCRs) are integral membrane glycoproteins representing the largest family of cell-surface receptors, characterized by a presence of the seven-α-helical- transmembrane spanning (7TM) structural motif. More than 1200 GPCRs mediate responses to peptides, proteins, hormones, neurotransmitters, metabolites, ions, photons, fatty acids, pathogens, and physical stimuli such as a sense of vision, olfaction, and taste in the human body [1,2,3,4,5] They play an essential role in cell activation, differentiation, proliferation, and directed migration, including immune and inflammatory response processes [6]. These receptors can mediate transduction of extracellular signals to control various physiological functions via G protein dependent or G protein-independent heterotrimeric pathways. We aimed to emphasize the important role of the extracellular loop ECL2 as one of the critical elements of the puzzle consisting of the cannabinoid receptor 1-ligand (drug) interactions, as well as modes of CB1R signaling regulation
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