Abstract
The endocannabinoid system has emerged as a promising target for the treatment of numerous diseases, including cancer, neurodegenerative disorders, and metabolic syndromes. Thus far, two cannabinoid receptors, CB1 and CB2, have been discovered, which are found predominantly in the central nervous system (CB1) or the immune system (CB2), among other organs and tissues. CB1 receptor ligands have been shown to induce a complex pattern of intracellular effects. The binding of a ligand induces distinct conformational changes in the receptor, which will eventually translate into distinct intracellular signaling pathways through coupling to specific intracellular effector proteins. These proteins can mediate receptor desensitization, trafficking, or signaling. Ligand specificity and selectivity, complex cellular components, and the concomitant expression of other proteins (which either regulate the CB1 receptor or are regulated by the CB1 receptor) will affect the therapeutic outcome of its targeting. With an increased interest in G protein-coupled receptors (GPCR) research, in-depth studies using mutations, biological assays, and spectroscopic techniques (such as NMR, EPR, MS, FRET, and X-ray crystallography), as well as computational modelling, have begun to reveal a set of concerted structural features in Class A GPCRs which relate to signaling pathways and the mechanisms of ligand-induced activation, deactivation, or activity modulation. This review will focus on the structural features of the CB1 receptor, mutations known to bias its signaling, and reported studies of CB1 receptor ligands to control its specific signaling.
Highlights
The CB1 receptor was first determined and characterized as the receptor protein for ∆9-THC, the major psychoactive constituent in Cannabis Sativa (Marijuana), from rat brain preparations in 1988 [1]
With an increased interest in G protein-coupled receptors (GPCR) research, in-depth studies using mutations, biological assays, and spectroscopic techniques, as well as computational modelling, have begun to reveal a set of concerted structural features in Class A GPCRs which relate to signaling pathways and the mechanisms of ligand-induced activation, deactivation, or activity modulation
The CB1 receptor represents a promising target for the development of novel therapeutics for the treatment of different pathologies, including metabolic syndromes and neurodegenerative diseases, as well as the symptomatic relief of neuropathic pain in patients with multiple sclerosis and spinal cord injuries [4,5]
Summary
The CB1 receptor was first determined and characterized as the receptor protein for ∆9-THC, the major psychoactive constituent in Cannabis Sativa (Marijuana), from rat brain preparations in 1988 [1]. The CB1 receptor represents a promising target for the development of novel therapeutics for the treatment of different pathologies, including metabolic syndromes and neurodegenerative diseases, as well as the symptomatic relief of neuropathic pain in patients with multiple sclerosis and spinal cord injuries [4,5]. This broad spectrum of possible therapeutic applications by targeting the CB1 receptor originates from its high expression levels in the central nervous system (CNS), being located primarily at the presynaptic terminals of central and peripheral neurons, and from its neuro-modulatory action [6,7,8]. A molecular-level understanding of the structural determinants of biased signaling at the CB1 receptor should contribute to the development of novel therapeutics able to activate diverse signaling paradigms
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