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Biological Psychiatry. Cognitive... Jun 2021The endocannabinoid system (ECS) is a widespread neuromodulatory network involved in the developing central nervous system as well as playing a major role in tuning many... (Review)
Review
The endocannabinoid system (ECS) is a widespread neuromodulatory network involved in the developing central nervous system as well as playing a major role in tuning many cognitive and physiological processes. The ECS is composed of endogenous cannabinoids, cannabinoid receptors, and the enzymes responsible for the synthesis and degradation of endocannabinoids. In addition to its endogenous roles, cannabinoid receptors are the primary target of Δ-tetrahydrocannabinol, the intoxicating component of cannabis. In this review, we summarize our current understanding of the ECS. We start with a description of ECS components and their role in synaptic plasticity and neurodevelopment, and then discuss how phytocannabinoids and other exogenous compounds may perturb the ECS, emphasizing examples relevant to psychosis.
Topics: Cannabis; Endocannabinoids; Humans; Neuronal Plasticity; Receptors, Cannabinoid
PubMed: 32980261
DOI: 10.1016/j.bpsc.2020.07.016 -
Biological Psychiatry Apr 2016The endocannabinoid system (ECS) is a widespread neuromodulatory system that plays important roles in central nervous system development, synaptic plasticity, and the... (Review)
Review
The endocannabinoid system (ECS) is a widespread neuromodulatory system that plays important roles in central nervous system development, synaptic plasticity, and the response to endogenous and environmental insults. The ECS comprises cannabinoid receptors, endogenous cannabinoids (endocannabinoids), and the enzymes responsible for the synthesis and degradation of the endocannabinoids. The most abundant cannabinoid receptors are the CB1 cannabinoid receptors; however, CB2 cannabinoid receptors, transient receptor potential channels, and peroxisome proliferator activated receptors are also engaged by some cannabinoids. Exogenous cannabinoids, such as tetrahydrocannabinol, produce their biological effects through their interactions with cannabinoid receptors. The best-studied endogenous cannabinoids are 2-arachidonoyl glycerol and arachidonoyl ethanolamide (anandamide). Despite similarities in chemical structure, 2-arachidonoyl glycerol and anandamide are synthesized and degraded by distinct enzymatic pathways, which impart fundamentally different physiologic and pathophysiologic roles to these two endocannabinoids. As a result of the pervasive social use of cannabis and the involvement of endocannabinoids in a multitude of biological processes, much has been learned about the physiologic and pathophysiologic roles of the ECS. This review provides an introduction to the ECS with an emphasis on its role in synaptic plasticity and how the ECS is perturbed in schizophrenia.
Topics: Arachidonic Acids; Cannabinoid Receptor Agonists; Dronabinol; Endocannabinoids; Glycerides; Humans; Neuronal Plasticity; Polyunsaturated Alkamides; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Schizophrenia
PubMed: 26698193
DOI: 10.1016/j.biopsych.2015.07.028 -
Advances in Pharmacology (San Diego,... 2017The CB and CB cannabinoid receptors (CBR, CBR) are members of the G protein-coupled receptor (GPCR) family that were identified over 20 years ago. CBRs and CBRs mediate... (Review)
Review
The CB and CB cannabinoid receptors (CBR, CBR) are members of the G protein-coupled receptor (GPCR) family that were identified over 20 years ago. CBRs and CBRs mediate the effects of Δ-tetrahydrocannabinol (Δ-THC), the principal psychoactive constituent of marijuana, and subsequently identified endogenous cannabinoids (endocannabinoids) anandamide and 2-arachidonoyl glycerol. CBRs and CBRs have both similarities and differences in their pharmacology. Both receptors recognize multiple classes of agonist and antagonist compounds and produce an array of distinct downstream effects. Natural polymorphisms and alternative splice variants may also contribute to their pharmacological diversity. As our knowledge of the distinct differences grows, we may be able to target select receptor conformations and their corresponding pharmacological responses. This chapter will discuss their pharmacological characterization, distribution, phylogeny, and signaling pathways. In addition, the effects of extended agonist exposure and how that affects signaling and expression patterns of the receptors are considered.
Topics: Alternative Splicing; Animals; Humans; Phylogeny; Polymorphism, Genetic; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Signal Transduction
PubMed: 28826534
DOI: 10.1016/bs.apha.2017.03.007 -
Current Molecular Pharmacology 2019Cannabinoid has long been used for medicinal purposes. Cannabinoid signaling has been considered the therapeutic target for treating pain, addiction, obesity,... (Review)
Review
BACKGROUND
Cannabinoid has long been used for medicinal purposes. Cannabinoid signaling has been considered the therapeutic target for treating pain, addiction, obesity, inflammation, and other diseases. Recent studies have suggested that in addition to CB1 and CB2, there are non-CB1 and non-CB2 cannabinoid-related orphan GPCRs including GPR18, GPR55, and GPR119. In addition, CB1 and CB2 display allosteric binding and biased signaling, revealing correlations between biased signaling and functional outcomes. Interestingly, new investigations have indicated that CB1 is functionally present within the mitochondria of striated and heart muscles directly regulating intramitochondrial signaling and respiration.
CONCLUSION
In this review, we summarize the recent progress in cannabinoid-related orphan GPCRs, CB1/CB2 structure, Gi/Gs coupling, allosteric ligands and biased signaling, and mitochondria-localized CB1, and discuss the future promise of this research.
Topics: Allosteric Regulation; Animals; Humans; Ligands; Models, Molecular; Receptors, Cannabinoid; Signal Transduction
PubMed: 30767756
DOI: 10.2174/1874467212666190215112036 -
International Journal of Molecular... Mar 2018The biological effects of cannabinoids, the major constituents of the ancient medicinal plant (marijuana) are mediated by two members of the G-protein coupled receptor... (Review)
Review
The biological effects of cannabinoids, the major constituents of the ancient medicinal plant (marijuana) are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R) and 2. The CB1R is the prominent subtype in the central nervous system (CNS) and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.
Topics: Animals; Cannabinoid Receptor Agonists; Central Nervous System; Endocannabinoids; Humans; Receptors, Cannabinoid; Signal Transduction
PubMed: 29533978
DOI: 10.3390/ijms19030833 -
Handbook of Experimental Pharmacology 2020Since antiquity, Cannabis has provoked enormous intrigue for its potential medicinal properties as well as for its unique pharmacological effects. The elucidation of its...
Since antiquity, Cannabis has provoked enormous intrigue for its potential medicinal properties as well as for its unique pharmacological effects. The elucidation of its major cannabinoid constituents, Δ-tetrahydrocannabinol (THC) and cannabidiol (CBD), led to the synthesis of new cannabinoids (termed synthetic cannabinoids) to understand the mechanisms underlying the pharmacology of Cannabis. These pharmacological tools were instrumental in the ultimate discovery of the endogenous cannabinoid system, which consists of CB and CB cannabinoid receptors and endogenously produced ligands (endocannabinoids), which bind and activate both cannabinoid receptors. CB receptors mediate the cannabimimetic effects of THC and are highly expressed on presynaptic neurons in the nervous system, where they modulate neurotransmitter release. In contrast, CB receptors are primarily expressed on immune cells. The endocannabinoids are tightly regulated by biosynthetic and hydrolytic enzymes. Accordingly, the endocannabinoid system plays a modulatory role in many physiological processes, thereby generating many promising therapeutic targets. An unintended consequence of this research was the emergence of synthetic cannabinoids sold for human consumption to circumvent federal laws banning Cannabis use. Here, we describe research that led to the discovery of the endogenous cannabinoid system and show how knowledge of this system benefitted as well as unintentionally harmed human health.
Topics: Cannabidiol; Cannabinoids; Dronabinol; Endocannabinoids; Humans; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2
PubMed: 32236882
DOI: 10.1007/164_2019_298 -
Neurotherapeutics : the Journal of the... Oct 2015The endocannabinoid system is currently defined as the ensemble of the two 7-transmembrane-domain and G protein-coupled receptors for Δ(9)-tetrahydrocannabinol (but not... (Review)
Review
The endocannabinoid system is currently defined as the ensemble of the two 7-transmembrane-domain and G protein-coupled receptors for Δ(9)-tetrahydrocannabinol (but not for most other plant cannabinoids or phytocannabinoids)-cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R); their two most studied endogenous ligands, the "endocannabinoids" N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG); and the enzymes responsible for endocannabinoid metabolism. However, anandamide and 2-AG, and also the phytocannabinoids, have more molecular targets than just CB1R and CB2R. Furthermore, the endocannabinoids, like most other lipid mediators, have more than just one set of biosynthetic and degrading pathways and enzymes, which they often share with "endocannabinoid-like" mediators that may or may not interact with the same proteins as Δ(9)-tetrahydrocannabinol and other phytocannabinoids. In some cases, these degrading pathways and enzymes lead to molecules that are not inactive and instead interact with other receptors. Finally, some of the metabolic enzymes may also participate in the chemical modification of molecules that have very little to do with endocannabinoid and cannabinoid targets. Here, we review the whole world of ligands, receptors, and enzymes, a true "endocannabinoidome", discovered after the cloning of CB1R and CB2R and the identification of anandamide and 2-AG, and its interactions with phytocannabinoids.
Topics: Animals; Cannabinoid Receptor Modulators; Endocannabinoids; Humans; Plant Extracts; Receptors, Cannabinoid
PubMed: 26271952
DOI: 10.1007/s13311-015-0374-6 -
British Journal of Pharmacology Aug 2022The use of the intoxicating cannabinoid delta-8-tetrahydrocannabinol (Δ -THC) has grown rapidly over the last several years. There have been dozens of Δ -THC studies... (Review)
Review
The use of the intoxicating cannabinoid delta-8-tetrahydrocannabinol (Δ -THC) has grown rapidly over the last several years. There have been dozens of Δ -THC studies dating back over many decades, yet no review articles have comprehensively covered these findings. In this review, we summarize the pharmacological studies of Δ -THC, including receptor binding, cell signalling, in vivo cannabimimetic activity, clinical activity and pharmacokinetics. We give special focus to studies that directly compared Δ -THC to its more commonly studied isomer, Δ -THC. Overall, the pharmacokinetics and pharmacodynamics of Δ -THC and Δ -THC are very similar. Δ -THC is a partial agonist of the cannabinoid CB receptor and has cannabimimetic activity in both animals and humans. The reduced potency of Δ -THC in clinical studies compared with Δ -THC can be explained by weaker cannabinoid CB receptor affinity, although there are other plausible mechanisms that may contribute. We highlight the gaps in our knowledge of Δ -THC pharmacology where further studies are needed, particularly in humans.
Topics: Animals; Cannabinoids; Dronabinol; Humans; Receptor, Cannabinoid, CB1; Receptors, Cannabinoid
PubMed: 35523678
DOI: 10.1111/bph.15865 -
Cell Feb 2020Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence...
Human endocannabinoid systems modulate multiple physiological processes mainly through the activation of cannabinoid receptors CB1 and CB2. Their high sequence similarity, low agonist selectivity, and lack of activation and G protein-coupling knowledge have hindered the development of therapeutic applications. Importantly, missing structural information has significantly held back the development of promising CB2-selective agonist drugs for treating inflammatory and neuropathic pain without the psychoactivity of CB1. Here, we report the cryoelectron microscopy structures of synthetic cannabinoid-bound CB2 and CB1 in complex with G, as well as agonist-bound CB2 crystal structure. Of important scientific and therapeutic benefit, our results reveal a diverse activation and signaling mechanism, the structural basis of CB2-selective agonists design, and the unexpected interaction of cholesterol with CB1, suggestive of its endogenous allosteric modulating role.
Topics: Allosteric Regulation; Allosteric Site; Animals; CHO Cells; Cannabinoid Receptor Agonists; Cannabinoids; Cell Line, Tumor; Cholesterol; Cricetinae; Cricetulus; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Molecular Dynamics Simulation; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Sf9 Cells; Signal Transduction; Spodoptera
PubMed: 32004463
DOI: 10.1016/j.cell.2020.01.008 -
Cell Jan 2019The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic...
The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases. Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution. The CB2-AM10257 structure reveals a distinctly different binding pose compared with CB1. However, the extracellular portion of the antagonist-bound CB2 shares a high degree of conformational similarity with the agonist-bound CB1, which led to the discovery of AM10257's unexpected opposing functional profile of CB2 antagonism versus CB1 agonism. Further structural analysis using mutagenesis studies and molecular docking revealed the molecular basis of their function and selectivity for CB2 and CB1. Additional analyses of our designed antagonist and agonist pairs provide important insight into the activation mechanism of CB2. The present findings should facilitate rational drug design toward precise modulation of the endocannabinoid system.
Topics: Animals; Cannabinoid Receptor Antagonists; Cannabinoids; Drug Design; Endocannabinoids; Humans; Ligands; Molecular Docking Simulation; Protein Binding; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, G-Protein-Coupled; Sf9 Cells; Structure-Activity Relationship
PubMed: 30639103
DOI: 10.1016/j.cell.2018.12.011