Cannabinoid receptors: nomenclature and pharmacological principles

Console-Bram, Linda; Marcu, Jahan P.; Abood, Mary E.

doi:10.1016/j.pnpbp.2012.02.009

Cited by 147 publications

(115 citation statements)

References 150 publications

(193 reference statements)

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“…In brief, cerebral cortical cells from 1-to 2-day-old mice were dissociated and plated in 75-cm 2 Falcon culture flasks in Dulbecco modified Eagle medium-F12 (HyClone Laboratories) supplemented with 10% heat-inactivated FBS, containing 2mM glutamine and 1ϫ antibiotic/antimycotic (complete medium). The medium was removed and replenished with complete medium containing 10 ng/mL GM-CSF at days 5 and 10 after plating.…”

Section: Cell Culturesmentioning

confidence: 99%

Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

Adhikary¹,

Kocieda

Yen

et al. 2012

Blood

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Administration of cannabinoid receptor 2 (CB2R) agonists in inflammatory and autoimmune disease and CNS injury models results in significant attenuation of clinical disease, and reduction of inflammatory mediators. Previous studies reported that CB2R signaling also reduces leukocyte migration. Migration of dendritic cells (DCs) to various sites is required for their activation and for the initiation of adaptive immune responses. Here, we report for the first time that CB2R signaling affects DC migration in vitro and in vivo, primarily through the inhibition of matrix metalloproteinase 9 (MMP-9) expression. Reduced MMP-9 production by DCs results in decreased migration to draining lymph nodes in vivo and in vitro in the matrigel migration assay. The effect on Mmp-9 expression is mediated through CB2R, resulting in reduction in cAMP levels, subsequent decrease in ERK activation, and reduced binding of c-Fos and c-Jun to Mmp-9 promoter activator protein 1 sites. We postulate that, by dampening production of MMP-9 and subsequent MMP-9-dependent DC migration, cannabinoids contribute to resolve acute inflammation and to reestablish homeostasis. Selective CB2R agonists might be valuable future therapeutic agents for the treatment of chronic inflammatory conditions by targeting activated immune cells, including DCs. IntroductionThe cannabinoid system consists of cannabinoid receptors and their ligands, including endocannabinoids, synthetic cannabinoid receptor agonists and antagonists, and phytocannabinoids. Several cannabinoid receptors have been described, that is, the classic cannabinoid receptor 1 (GPR) and GPR, the previously orphaned G-protein receptors GPR18 and GPR55, various ion channels, and intracellular peroxisome proliferator-activated receptor-␥ (reviewed in Pertwee et al 1 and Console-Bram 2 ). The 2 classic cannabinoid receptors, CB1R and CB2R, have different distribution and functions (reviewed in Kubajewska and Constantinescu 3 and Basu and Dittel 4 ). CB1R is abundantly expressed on CNS and peripheral neurons and involved in neural functions. In contrast, CB2R is mostly expressed on immune cells and involved in immunoregulation. Administration of CB2R-selective agonists in models of inflammatory and autoimmune diseases such as systemic sclerosis, experimental autoimmune uveoretinitis, inflammatory bowel diseases, and experimental autoimmune encephalomyelitis (EAE) resulted in attenuation of clinical disease (reviewed in Basu and Dittel 4 ). CB2R agonists also have been reported to have a beneficial effect in models of CNS injury such as cerebral infarction and spinal cord injury. [5][6][7][8] In addition to effects on clinical outcome, CB2R agonists reduced the levels of inflammatory mediators in various experimental models. [8][9][10] A possible mechanism for the anti-inflammatory effect of CB2R signaling is the direct action of CB2R agonists on immune cells. In vitro studies indicated that CB2R signaling inhibited the production of proinflammatory cytokines such as TNF␣, IL-6, IL-2, and IFN-␥ by ac...

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Section: Cell Culturesmentioning

confidence: 99%

Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

Adhikary¹,

Kocieda

Yen

et al. 2012

Blood

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“…Since anandamide was the very first endocannabinoid described (Devane et al, 1992), it has been the focus of attention due to that it resembles the pharmacological effects of principal compound of Cannabis sativa, D 9 -THC, by behaving as a natural ligand for the CB 1 cannabinoid receptor (Console-Bram et al, 2012). Among the evidence regarding the role of activation of the CB 1 cannabinoid receptor modulating diverse functions controlled by the central nervous system, it has been demonstrated that administrations of anandamide promote sleep (Murillo-Rodrı´guez et al, 1998Herrera-Solis et al, 2010;Rueda-Orozco et al, 2010), whereas injections of the CB 1 cannabinoid receptor antagonist SR141716A increase alertness in rodents (Santucci et al, 1996;Murillo-Rodrı´guez et al, 2001.…”

Section: Introductionmentioning

confidence: 99%

Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis

et al. 2016

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Abstract-The endocannabinoid system comprises receptors (CB 1 and CB 2 cannabinoid receptors), enzymes (Fatty Acid Amide Hydrolase [FAAH], which synthesizes the endocannabinoid anandamide), as well as the anandamide membrane transporter (AMT). Importantly, previous experiments have demonstrated that the endocannabinoid system modulates multiple neurobiological functions, including sleep. For instance, SR141716A (the CB 1 cannabinoid receptor antagonist) as well as URB597 (the FAAH inhibitor) increase waking in rats whereas VDM-11 (the blocker of the AMT) enhances sleep in rodents. However, no further evidence is available regarding the neurobiological role of the endocannabinoid system in the homeostatic control of sleep. Therefore, the aim of the current experiment was to test if SR141716A, URB597 or VDM-11 would modulate the sleep rebound after sleep deprivation. Thus, these compounds were systemically injected (5, 10, 20 mg/kg; ip; separately each one) into rats after prolonged waking. We found that SR141716A and URB597 blocked in dose-dependent fashion the sleep rebound whereas animals treated with VDM-11 displayed sleep rebound during the recovery period. Complementary, injection after sleep deprivation of either SR141716A or URB597 enhanced dose-dependently the extracellular levels of dopamine (DA), norepinephrine (NE), epinephrine (EP), serotonin (5-HT), as well as adenosine (AD) while VDM-11 caused a decline in contents of these molecules. These findings suggest that SR141716A or URB597 behave as a potent stimulants since they suppressed the sleep recovery period after prolonged waking. It can be concluded that elements of the endocannabinoid system, such as the CB 1 cannabinoid receptor, FAAH and AMT, modulate the sleep homeostasis after prolonged waking. Ó

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“…1,2 Of these components, CB1R has garnered particular experimental and clinical interest since the discovery over 25 years ago that the main psychoactive cannabis constituent, the phytocannabinoid (-)-Δ 9 -tetrahy-drocannabinol (Δ 9 -THC), exerts its psychotropic and addictive effects by activating brain CB1R. 3 Expressed to varying extents in peripheral organs where it plays important roles in cardiovascular, reproductive, and metabolic processes, CB1R retains a high (≥97%) degree of amino acid sequence identity across mouse, rat, and human and is one of the most abundant GPCRs in the central nervous system (CNS).…”

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confidence: 99%

Molecular-Interaction and Signaling Profiles of AM3677, a Novel Covalent Agonist Selective for the Cannabinoid 1 Receptor

Janero

Yaddanapudi

Zvonok

et al. 2015

ACS Chem. Neurosci.

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The cannabinoid 1 receptor (CB1R) is one of the most abundant G protein-coupled receptors (GPCRs) in the central nervous system. CB1R involvement in multiple physiological processes, especially neurotransmitter release and synaptic function, has made this GPCR a prime drug discovery target, and pharmacological CB1R activation has been demonstrated to be a tenable therapeutic modality. Accordingly, the design and profiling of novel, drug-like CB1R modulators to inform the receptor’s ligand-interaction landscape and molecular pharmacology constitute a prime contemporary research focus. For this purpose, we report utilization of AM3677, a designer endocannabinoid (anandamide) analogue derivatized with a reactive electrophilic isothiocyanate functionality, as a covalent, CB1R-selective chemical probe. The data demonstrate that reaction of AM3677 with a cysteine residue in transmembrane helix 6 of human CB1R (hCB1R), C6.47(355), is a key feature of AM3677’s ligand-binding motif. Pharmacologically, AM3677 acts as a high-affinity, lowefficacy CB1R agonist that inhibits forskolin-stimulated cellular cAMP formation and stimulates CB1R coupling to G protein. AM3677 also induces CB1R endocytosis and irreversible receptor internalization. Computational docking suggests the importance of discrete hydrogen bonding and aromatic interactions as determinants of AM3677’s topology within the ligand-binding pocket of active-state hCB1R. These results constitute the initial identification and characterization of a potent, high-affinity, hCB1R-selective covalent agonist with utility as a pharmacologically active, orthostericsite probe for providing insight into structure-function correlates of ligand-induced CB1R activation and the molecular features of that activation by the native ligand, anandamide.

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Cannabinoid receptors: nomenclature and pharmacological principles

Cited by 147 publications

References 150 publications

Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

Signaling through cannabinoid receptor 2 suppresses murine dendritic cell migration by inhibiting matrix metalloproteinase 9 expression

Revealing the role of the endocannabinoid system modulators, SR141716A, URB597 and VDM-11, in sleep homeostasis

Molecular-Interaction and Signaling Profiles of AM3677, a Novel Covalent Agonist Selective for the Cannabinoid 1 Receptor

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