scholarly journals Glycerophosphodiesterase 3 (GDE3) is a lysophosphatidylinositol-specific ectophospholipase C acting as an endocannabinoid signaling switch

2020 ◽  
Vol 295 (46) ◽  
pp. 15767-15781
Author(s):  
Fabienne Briand-Mésange ◽  
Véronique Pons ◽  
Sophie Allart ◽  
Julien Masquelier ◽  
Gaëtan Chicanne ◽  
...  
Keyword(s):  
Cannabinoid Receptor ◽  
Hek293t Cell ◽  
Endocannabinoid System ◽  
Intact Cells ◽  
Alternative Pathways ◽  
Inositol 1 ◽  
Noncanonical Pathway ◽  
New Research ◽  
G Protein Coupled

Endocannabinoid signaling plays a regulatory role in various (neuro)biological functions. 2-arachidonoylglycerol (2-AG) is the most abundant endocannabinoid, and although its canonical biosynthetic pathway involving phosphoinositide-specific phospholipase C and diacylglycerol lipase α is known, alternative pathways remain unsettled. Here, we characterize a noncanonical pathway implicating glycerophosphodiesterase 3 (GDE3, from GDPD2 gene). Human GDE3 expressed in HEK293T cell membranes catalyzed the conversion of lysophosphatidylinositol (LPI) into monoacylglycerol and inositol-1-phosphate. The enzyme was equally active against 1-acyl and 2-acyl LPI. When using 2-acyl LPI, where arachidonic acid is the predominant fatty acid, LC-MS analysis identified 2-AG as the main product of LPI hydrolysis by GDE3. Furthermore, inositol-1-phosphate release into the medium occurred upon addition of LPI to intact cells, suggesting that GDE3 is actually an ecto-lysophospholipase C. In cells expressing G-protein–coupled receptor GPR55, GDE3 abolished 1-acyl LPI–induced signaling. In contrast, upon simultaneous ex-pression of GDE3 and cannabinoid receptor CB2, 2-acyl LPI evoked the same signal as that induced by 2-AG. These data strongly suggest that, in addition to degrading the GPR55 LPI ligand, GDE3 can act as a switch between GPR55 and CB2 signaling. Coincident with a major expression of both GDE3 and CB2 in the spleen, spleens from transgenic mice lacking GDE3 displayed doubling of LPI content compared with WT mice. Decreased production of 2-AG in whole spleen was also observed, supporting the in vivo relevance of our findings. These data thus open a new research avenue in the field of endocannabinoid generation and reinforce the view of GPR55 and LPI being genuine actors of the endocannabinoid system.

scholarly journals Therapeutic Attributes of Endocannabinoid System against Neuro-Inflammatory Autoimmune Disorders

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3389
Author(s):  
Ishtiaq Ahmed ◽  
Saif Ur Rehman ◽  
Shiva Shahmohamadnejad ◽  
Muhammad Anjum Zia ◽  
Muhammad Ahmad ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Therapeutic Potential ◽  
Endocannabinoid System ◽  
Cell Types ◽  
Autoimmune Disorders ◽  
Specific Receptors ◽  
Different Cell Types

In humans, various sites like cannabinoid receptors (CBR) having a binding affinity with cannabinoids are distributed on the surface of different cell types, where endocannabinoids (ECs) and derivatives of fatty acid can bind. The binding of these substance(s) triggers the activation of specific receptors required for various physiological functions, including pain sensation, memory, and appetite. The ECs and CBR perform multiple functions via the cannabinoid receptor 1 (CB1); cannabinoid receptor 2 (CB2), having a key effect in restraining neurotransmitters and the arrangement of cytokines. The role of cannabinoids in the immune system is illustrated because of their immunosuppressive characteristics. These characteristics include inhibition of leucocyte proliferation, T cells apoptosis, and induction of macrophages along with reduced pro-inflammatory cytokines secretion. The review seeks to discuss the functional relationship between the endocannabinoid system (ECS) and anti-tumor characteristics of cannabinoids in various cancers. The therapeutic potential of cannabinoids for cancer—both in vivo and in vitro clinical trials—has also been highlighted and reported to be effective in mice models in arthritis for the inflammation reduction, neuropathic pain, positive effect in multiple sclerosis and type-1 diabetes mellitus, and found beneficial for treating in various cancers. In human models, such studies are limited; thereby, further research is indispensable in this field to get a conclusive outcome. Therefore, in autoimmune disorders, therapeutic cannabinoids can serve as promising immunosuppressive and anti-fibrotic agents.

scholarly journals BPA Directly Decreases GnRH Neuronal Activity via Noncanonical Pathway

Endocrinology ◽  
2016 ◽  
Vol 157 (5) ◽  
pp. 1980-1990 ◽  
Author(s):  
Ulrike Klenke ◽  
Stephanie Constantin ◽  
Susan Wray
Keyword(s):  
Estrogen Receptor ◽  
G Protein ◽  
Neuronal Activity ◽  
Environmental Pollutant ◽  
Pcr Analysis ◽  
Gnrh Neurons ◽  
Noncanonical Pathway ◽  
G Protein Coupled ◽  
Estrogen Related Receptor

Abstract Peripheral feedback of gonadal estrogen to the hypothalamus is critical for reproduction. Bisphenol A (BPA), an environmental pollutant with estrogenic actions, can disrupt this feedback and lead to infertility in both humans and animals. GnRH neurons are essential for reproduction, serving as an important link between brain, pituitary, and gonads. Because GnRH neurons express several receptors that bind estrogen, they are potential targets for endocrine disruptors. However, to date, direct effects of BPA on GnRH neurons have not been shown. This study investigated the effects of BPA on GnRH neuronal activity using an explant model in which large numbers of primary GnRH neurons are maintained and express many of the receptors found in vivo. Because oscillations in intracellular calcium have been shown to correlate with electrical activity in GnRH neurons, calcium imaging was used to assay the effects of BPA. Exposure to 50μM BPA significantly decreased GnRH calcium activity. Blockage of γ-aminobutyric acid ergic and glutamatergic input did not abrogate the inhibitory BPA effect, suggesting direct regulation of GnRH neurons by BPA. In addition to estrogen receptor-β, single-cell RT-PCR analysis confirmed that GnRH neurons express G protein-coupled receptor 30 (G protein-coupled estrogen receptor 1) and estrogen-related receptor-γ, all potential targets for BPA. Perturbation studies of the signaling pathway revealed that the BPA-mediated inhibition of GnRH neuronal activity occurred independent of estrogen receptors, GPER, or estrogen-related receptor-γ, via a noncanonical pathway. These results provide the first evidence of a direct effect of BPA on GnRH neurons.

scholarly journals Discovery of Orexant and Anorexant Agents with Indazole Scaffold Endowed with Peripheral Antiedema Activity

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 492 ◽  
Author(s):  
Dimmito ◽  
Stefanucci ◽  
Pieretti ◽  
Minosi ◽  
Dvorácskó ◽  
...  
Keyword(s):  
Feeding Behavior ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Methyl Esters ◽  
Endocannabinoid System ◽  
Tail Flick ◽  
Binding Assays ◽  
Tail Flick Test

The endocannabinoid system represents an integrated neuronal network involved in the control of several organisms’ functions, such as feeding behavior. A series of hybrids of 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (mimonabant), a well-known inverse agonist of the type-1 cannabinoid receptor (CB1), once used as an antiobesity drug, and the N-(2S)-substitutes of 1-[(4-fluorophenyl)methyl]indazole-3-carboxamide with 1-amino-3-methyl-1-oxobutane (AB-Fubinaca), 1-amino-3,3-dimethyl-1-oxobutane (ADB-Fubinaca), and 3-methylbutanoate (AMB-Fubinaca), endowed with potent agonistic activity towards cannabinoid receptors CB1 and CB2 were in solution as C-terminal amides, acids, methyl esters and N-methyl amides. These compounds have been studied by binding assays to cannabinoid receptors and by functional receptor assays, using rat brain membranes in vitro. The most active among them as an agonist, (S)-1-(2,4-dichlorobenzyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-1H-indazole-3-carboxamide (LONI11), and an antagonist, (S)-2-(1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoic acid (LONI4), were tested in vivo in mic, to evaluate their ability to stimulate or suppress feeding behavior after intraperitoneal (i.p.) administration. For a LONI11 formalin test and a tail flick test after an administration by the subcutaneous (s.c.) and intracerebroventricular (i.c.v.) routes, respectively, were also carried out in vivo in mice to investigate the antinociceptive property at the central and peripheral levesl. We observed a significant orexant effect for LONI11 and an intense anorexant effect for (S)-methyl 2-(1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate (LONI2) and LONI4. In zymosan-induced edema and hyperalgesia, LONI11 reduced the percent of paw volume increase and paw latency after s.c. administration, also suggesting a possible peripheral anti-inflammatory activity.

scholarly journals Towards in vivo imaging of functionally active 5-HT1A receptors in schizophrenia: concepts and challenges

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Oriane Razakarivony ◽  
Adrian Newman-Tancredi ◽  
Luc Zimmer
Keyword(s):  
Psychiatric Disorders ◽  
Cognitive Processes ◽  
G Protein Coupled Receptors ◽  
Research Paradigms ◽  
New Research ◽  
New Generation ◽  
G Protein Coupled

AbstractThe serotonin 5-HT1A receptor has attracted wide attention as a target for treatment of psychiatric disorders. Although this receptor is important in the pharmacological mechanisms of action of new-generation antipsychotics, its characterization remains incomplete. Studies based on in vitro molecular imaging on brain tissue by autoradiography, and more recently in vivo PET imaging, have not yielded clear results, in particular due to the limitations of current 5-HT1A radiotracers, which lack specificity and/or bind to all 5-HT1A receptors, regardless of their functional status. The new concept of PET neuroimaging of functionally active G-protein-coupled receptors makes it possible to revisit PET brain exploration by enabling new research paradigms. For the 5-HT1A receptor it is now possible to use [18F]-F13640, a 5-HT1A receptor radioligand with high efficacy agonist properties, to specifically visualize and quantify functionally active receptors, and to relate this information to subjects’ pathophysiological or pharmacological state. We therefore propose imaging protocols to follow changes in the pattern of functional 5-HT1A receptors in relation to mood deficits or cognitive processes. This could allow improved discrimination of different schizophrenia phenotypes and greater understanding of the basis of therapeutic responses to antipsychotic drugs. Finally, as well as targeting functionally active receptors to gain insights into the role of 5-HT1A receptors, the concept can also be extended to the study of other receptors involved in the pathophysiology or therapy of psychiatric disorders.

scholarly journals Endocannabinoid system acts as a regulator of immune homeostasis in the gut

2017 ◽  
Vol 114 (19) ◽  
pp. 5005-5010 ◽  
Author(s):  
Nandini Acharya ◽  
Sasi Penukonda ◽  
Tatiana Shcheglova ◽  
Adam T. Hagymasi ◽  
Sreyashi Basu ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Nod Mice ◽  
Immune Homeostasis ◽  
Dependent Manner ◽  
Mice Model ◽  
Nonobese Diabetic

Endogenous cannabinoids (endocannabinoids) are small molecules biosynthesized from membrane glycerophospholipid. Anandamide (AEA) is an endogenous intestinal cannabinoid that controls appetite and energy balance by engagement of the enteric nervous system through cannabinoid receptors. Here, we uncover a role for AEA and its receptor, cannabinoid receptor 2 (CB2), in the regulation of immune tolerance in the gut and the pancreas. This work demonstrates a major immunological role for an endocannabinoid. The pungent molecule capsaicin (CP) has a similar effect as AEA; however, CP acts by engagement of the vanilloid receptor TRPV1, causing local production of AEA, which acts through CB2. We show that the engagement of the cannabinoid/vanilloid receptors augments the number and immune suppressive function of the regulatory CX3CR1hi macrophages (Mϕ), which express the highest levels of such receptors among the gut immune cells. Additionally, TRPV1−/− or CB2−/− mice have fewer CX3CR1hi Mϕ in the gut. Treatment of mice with CP also leads to differentiation of a regulatory subset of CD4+ cells, the Tr1 cells, in an IL-27–dependent manner in vitro and in vivo. In a functional demonstration, tolerance elicited by engagement of TRPV1 can be transferred to naïve nonobese diabetic (NOD) mice [model of type 1 diabetes (T1D)] by transfer of CD4+ T cells. Further, oral administration of AEA to NOD mice provides protection from T1D. Our study unveils a role for the endocannabinoid system in maintaining immune homeostasis in the gut/pancreas and reveals a conversation between the nervous and immune systems using distinct receptors.

scholarly journals Cannabinoid receptor 2 and its agonists mediate hematopoiesis and hematopoietic stem and progenitor cell mobilization

Blood ◽  
2011 ◽  
Vol 117 (3) ◽  
pp. 827-838 ◽  
Author(s):  
Shuxian Jiang ◽  
Meritxell Alberich-Jorda ◽  
Radoslaw Zagozdzon ◽  
Kalindi Parmar ◽  
Yigong Fu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cell ◽  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Bone Marrow Cells ◽  
Endocannabinoid System ◽  
Hematopoietic Stem ◽  
Cb2 Receptors ◽  
Cb2 Agonist

Abstract Endocannabinoids are arachidonic acid derivatives and part of a novel bioactive lipid signaling system, along with their G-coupled cannabinoid receptors (CB1 and CB2) and the enzymes involved in their biosynthesis and degradation. However, their roles in hematopoiesis and hematopoietic stem and progenitor cell (HSPC) functions are not well characterized. Here, we show that bone marrow stromal cells express endocannabinoids (anandamide and 2-arachidonylglycerol), whereas CB2 receptors are expressed in human and murine HSPCs. On ligand stimulation with CB2 agonists, CB2 receptors induced chemotaxis, migration, and enhanced colony formation of bone marrow cells, which were mediated via ERK, PI3-kinase, and Gαi-Rac1 pathways. In vivo, the CB2 agonist AM1241 induced mobilization of murine HSPCs with short- and long-term repopulating abilities. In addition, granulocyte colony-stimulating factor -induced mobilization of HSPCs was significantly decreased by specific CB2 antagonists and was impaired in Cnr2−/− cannabinoid type 2 receptor knockout mice. Taken together, these results demonstrate that the endocannabinoid system is involved in hematopoiesis and that CB2/CB2 agonist axis mediates repopulation of hematopoiesis and mobilization of HSPCs. Thus, CB2 agonists may be therapeutically applied in clinical conditions, such as bone marrow transplantation.

scholarly journals Epidermal Endocannabinoid System (EES) and its Cosmetic Application

Cosmetics ◽  
2019 ◽  
Vol 6 (2) ◽  
pp. 33
Author(s):  
Sekyoo Jeong ◽  
Min Kim ◽  
Sin Lee ◽  
Byeong Park
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Inflammatory Responses ◽  
Endocannabinoid System ◽  
Major Constituent ◽  
Health Improvement ◽  
Hemp Seed ◽  
Therapeutic Benefits

Recently, cannabis, or its major constituent cannabidiol (CBD), has emerged as an attractive cosmetic ingredient. Initiated as a basic investigation of the physiological roles of cannabinoid receptors and their endogenous ligands, endocannabinoids’ diverse potential benefits have been proposed for using cannabinoid receptor modulating compounds in skin health. Improvement in skin barrier functions, alleviating inflammatory responses, and the relief of itching sensations are some commonly expected therapeutic benefits, which have been supported by many in vitro, in vivo, and clinical studies. While hemp seed oils or hemp extracts might be used for the cosmetic formulation, the potential for contamination with a psychoactive cannabinoid, such as 9-THC, should be carefully checked. Instead of using hemp-derived ingredients, the use of cannabinomimetics, synthetic ligands on cannabinoid receptors, or entourage compounds (which modulate intracellular synthesis and the degradation of endocannabinoids), have been tried. In this review, a brief introduction of the epidermal endocannabinoid system (EES) and its physiological roles will be followed by a review of the cosmetic and dermatologic application of cannabinomimetics and entourage compounds. The practical application of newly developed endocannabinomimetics will be discussed as well.

scholarly journals Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1567 ◽  
Author(s):  
Elaine C. D. Gonçalves ◽  
Gabriela M. Baldasso ◽  
Maíra A. Bicca ◽  
Rodrigo S. Paes ◽  
Raffaele Capasso ◽  
...  
Keyword(s):  
Phenolic Compounds ◽  
Cannabinoid Receptors ◽  
Enzyme Inhibitors ◽  
Cannabis Sativa ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Receptor Type ◽  
Immune Mediated ◽  
Medicinal Use ◽  
G Protein Coupled

Medicinal use of Cannabis sativa L. has an extensive history and it was essential in the discovery of phytocannabinoids, including the Cannabis major psychoactive compound—Δ9-tetrahydrocannabinol (Δ9-THC)—as well as the G-protein-coupled cannabinoid receptors (CBR), named cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R), both part of the now known endocannabinoid system (ECS). Cannabinoids is a vast term that defines several compounds that have been characterized in three categories: (i) endogenous, (ii) synthetic, and (iii) phytocannabinoids, and are able to modulate the CBR and ECS. Particularly, phytocannabinoids are natural terpenoids or phenolic compounds derived from Cannabis sativa. However, these terpenoids and phenolic compounds can also be derived from other plants (non-cannabinoids) and still induce cannabinoid-like properties. Cannabimimetic ligands, beyond the Cannabis plant, can act as CBR agonists or antagonists, or ECS enzyme inhibitors, besides being able of playing a role in immune-mediated inflammatory and infectious diseases, neuroinflammatory, neurological, and neurodegenerative diseases, as well as in cancer, and autoimmunity by itself. In this review, we summarize and critically highlight past, present, and future progress on the understanding of the role of cannabinoid-like molecules, mainly terpenes, as prospective therapeutics for different pathological conditions.

Cannabinoid Receptors CB1 and CB2 Regulate Mobilization of Hematopoietic Stem and Progenitor Cells.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1383-1383
Author(s):  
Hava Avraham ◽  
Radoslaw Zagozdzon ◽  
Yigong Fu ◽  
Jerome E. Groopman ◽  
Shuxian Jiang
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Cell Trafficking ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Cd34 Cells ◽  
Stem And Progenitor Cells ◽  
Clinical Conditions ◽  
G Protein Coupled

Abstract Endocannabinoids are lipid mediators that modulate central and peripheral neural functions as well as immune responses and bind to specific G-protein-coupled receptors:CB1 and CB2. Here, we investigated the role of CB1/CB2 and cognate cannabinoid ligands in hematopoietic stem and progenitor cell (HSPC) mobilization. CB1 and CB2receptor expression was observed in human and murine HSPCs. Cannabinoid ligands induced the chemotaxis of the human CD34+ cells and caused mobilization of murine HSPC in vivo. Inhibition of degradation of the endocannabinoid anandamide by URB597induced mobilization of HSPC and significantly augmented mobilization of these cells when URB597 was administered with G-CSF-, AMD3100- and with the combination of G-CSF+AMD3100. Moreover, the cannabinoid- or G-CSF-induced mobilization of HSPC was significantly impaired by cannabinoid receptor inhibitors and in CB1- andCB2-knockout mice. Administration of exogenous cannabinoid agonists in mice induced mobilization of progenitors as well as stem cells in vivo with long-term repopulating ability. These results demonstrate a novel pathway by which the cannabinoid system regulates HSPC cell trafficking, and may be therapeutically applied in clinical conditions, such as bone marrow transplantation.

scholarly journals Overactivation of the endocannabinoid system alters the antilipolytic action of insulin in mouse adipose tissue

2017 ◽  
Vol 313 (1) ◽  
pp. E26-E36 ◽  
Author(s):  
Tania Muller ◽  
Laurent Demizieux ◽  
Stéphanie Troy-Fioramonti ◽  
Joseph Gresti ◽  
Jean-Paul Pais de Barros ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cannabinoid Receptor ◽  
Endocannabinoid System ◽  
Glycerol Release ◽  
Peripheral Tissues ◽  
Fat Mobilization ◽  
Plasma Insulin Levels ◽  
Ectopic Fat Deposition

Evidence has accumulated that obesity-related metabolic dysregulation is associated with overactivation of the endocannabinoid system (ECS), which involves cannabinoid receptor 1 (CB1R), in peripheral tissues, including adipose tissue (AT). The functional consequences of CB1R activation on AT metabolism remain unclear. Since excess fat mobilization is considered an important primary event contributing to the onset of insulin resistance, we combined in vivo and in vitro experiments to investigate whether activation of ECS could alter the lipolytic rate. For this purpose, the appearance of plasma glycerol was measured in wild-type and CB1R−/− mice after acute anandamide administration or inhibition of endocannabinoid degradation by JZL195. Additional experiments were conducted on rat AT explants to evaluate the direct consequences of ECS activation on glycerol release and signaling pathways. Treatments stimulated glycerol release in mice fasted for 6 h and injected with glucose but not in 24-h fasted mice or in CB1R−/−, suggesting that the effect was dependent on plasma insulin levels and mediated by CB1R. We concomitantly observed that Akt cascade activity was decreased, indicating an alteration of the antilipolytic action of insulin. Similar results were obtained with tissue explants exposed to anandamide, thus identifying CB1R of AT as a major target. This study indicates the existence of a functional interaction between CB1R and lipolysis regulation in AT. Further investigation is needed to test if the elevation of ECS tone encountered in obesity is associated with excess fat mobilization contributing to ectopic fat deposition and related metabolic disorders.

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