The Emerging Role of the Cannabinoid Receptor Family in Peripheral and Neuro-immune Interactions

The inflammasome is an important innate immune pathway that regulates at least two host responses protective against infections: (1) secretion of the proinflammatory cytokines IL-1βand IL-18 and (2) induction of pyroptosis, a form of cell death. Inflammasomes, of which different types have been identified, are multiprotein complexes containing pattern recognition receptors belonging to the Nod-like receptor family or the PYHIN family and the protease caspase-1. The molecular aspects involved in the activation of different inflammasomes by various pathogens are being rapidly elucidated, and their role during infections is being characterized. Production of IL-1βand IL-18 and induction of pyroptosis of the infected cell have been shown to be protective against many infectious agents. Here, we review the recent literature concerning inflammasome activation in the context of bacterial infections and identify important questions to be answered in the future.

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The endogenous cannabinoid receptor ligand, anandamide, inhibits the motor behavior: role of nigrostriatal dopaminergic neurons

Life Sciences ◽

10.1016/0024-3205(95)00186-a ◽

1995 ◽

Vol 56 (23-24) ◽

pp. 2033-2040 ◽

Cited By ~ 76

Author(s):

J. Romero ◽

L. Garcia ◽

M. Cebeira ◽

D. Zadrozny ◽

J.J. Fernández-Ruiz ◽

...

Keyword(s):

Dopaminergic Neurons ◽

Cannabinoid Receptor ◽

Motor Behavior ◽

Receptor Ligand ◽

Endogenous Cannabinoid

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Mutations in the ‘DRY’ motif of the CB1 cannabinoid receptor result in biased receptor variants

Journal of Molecular Endocrinology ◽

10.1530/jme-14-0219 ◽

2014 ◽

Vol 54 (1) ◽

pp. 75-89 ◽

Cited By ~ 15

Author(s):

Pál Gyombolai ◽

András D Tóth ◽

Dániel Tímár ◽

Gábor Turu ◽

László Hunyady

Keyword(s):

G Protein ◽

G Proteins ◽

Double Mutant ◽

Cannabinoid Receptor ◽

Camp Accumulation ◽

Protein Activation ◽

Cb1 Cannabinoid Receptor ◽

G Protein Activation ◽

Dry Motif

The role of the highly conserved ‘DRY’ motif in the signaling of the CB1cannabinoid receptor (CB1R) was investigated by inducing single-, double-, and triple-alanine mutations into this site of the receptor. We found that the CB1R-R3.50A mutant displays a partial decrease in its ability to activate heterotrimeric Goproteins (∼80% of WT CB1R (CB1R-WT)). Moreover, this mutant showed an enhanced basal β-arrestin2 (β-arr2) recruitment. More strikingly, the double-mutant CB1R-D3.49A/R3.50A was biased toward β-arrs, as it gained a robustly increased β-arr1 and β-arr2 recruitment ability compared with the WT receptor, while its G-protein activation was decreased. In contrast, the double-mutant CB1R-R3.50A/Y3.51A proved to be G-protein-biased, as it was practically unable to recruit β-arrs in response to agonist stimulus, while still activating G-proteins, although at a reduced level (∼70% of CB1R-WT). Agonist-induced ERK1/2 activation of the CB1R mutants showed a good correlation with their β-arr recruitment ability but not with their G-protein activation or inhibition of cAMP accumulation. Our results suggest that G-protein activation and β-arr binding of the CB1R are mediated by distinct receptor conformations, and the conserved ‘DRY’ motif plays different roles in the stabilization of these conformations, thus mediating both G-protein- and β-arr-mediated functions of CB1R.

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Estrogen Receptor and Vascular Aging

Frontiers in Aging ◽

10.3389/fragi.2021.727380 ◽

2021 ◽

Vol 2 ◽

Author(s):

Morgane Davezac ◽

Melissa Buscato ◽

Rana Zahreddine ◽

Patrick Lacolley ◽

Daniel Henrion ◽

...

Keyword(s):

Estrogen Receptor ◽

Cardiovascular Diseases ◽

Experimental Studies ◽

Hormonal Treatment ◽

Protective Effects ◽

Age Related ◽

Nuclear Receptor Family ◽

The Impact ◽

Receptor Family

Cardiovascular diseases remain an age-related pathology in both men and women. These pathologies are 3-fold more frequent in men than in women before menopause, although this difference progressively decreases after menopause. The vasculoprotective role of estrogens are well established before menopause, but the consequences of their abrupt decline on the cardiovascular risk at menopause remain debated. In this review, we will attempt to summarize the main clinical and experimental studies reporting the protective effects of estrogens against cardiovascular diseases, with a particular focus on atherosclerosis, and the impact of aging and estrogen deprivation on their endothelial actions. The arterial actions of estrogens, but also part of that of androgens through their aromatization into estrogens, are mediated by the estrogen receptor (ER)α and ERβ. ERs belong to the nuclear receptor family and act by transcriptional regulation in the nucleus, but also exert non-genomic/extranuclear actions. Beside the decline of estrogens at menopause, abnormalities in the expression and/or function of ERs in the tissues, and particularly in arteries, could contribute to the failure of classic estrogens to protect arteries during aging. Finally, we will discuss how recent insights in the mechanisms of action of ERα could contribute to optimize the hormonal treatment of the menopause.

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Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/1806344 ◽

2021 ◽

Vol 2021 ◽

pp. 1-22

Author(s):

Yang Zhang ◽

Weifang Liu ◽

Yanqi Zhong ◽

Qi Li ◽

Mengying Wu ◽

...

Keyword(s):

Oxidative Stress ◽

Nlrp3 Inflammasome ◽

Low Dose ◽

Therapeutic Potential ◽

Metabolic Phenotypes ◽

Pyrin Domain ◽

Underlying Mechanisms ◽

And Oxidative Stress ◽

Receptor Family

NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis is a crucial event in the preeclamptic pathogenesis, tightly linked with the uteroplacental TLR4/NF-κB signaling. Trophoblastic glycometabolism reprogramming has now been noticed in the preeclampsia pathogenesis, plausibly modulated by the TLR4/NF-κB signaling as well. Intriguingly, cellular pyroptosis and metabolic phenotypes may be inextricably linked and interacted. Metformin (MET), a widely accepted NF-κB signaling inhibitor, may have therapeutic potential in preeclampsia while the underlying mechanisms remain unclear. Herein, we investigated the role of MET on trophoblastic pyroptosis and its relevant metabolism reprogramming. The safety of pharmacologic MET concentration to trophoblasts was verified at first, which had no adverse effects on trophoblastic viability. Pharmacological MET concentration suppressed NLRP3 inflammasome-induced pyroptosis partly through inhibiting the TLR4/NF-κB signaling in preeclamptic trophoblast models induced via low-dose lipopolysaccharide. Besides, MET corrected the glycometabolic reprogramming and oxidative stress partly via suppressing the TLR4/NF-κB signaling and blocking transcription factor NF-κB1 binding on the promoter PFKFB3, a potent glycolytic accelerator. Furthermore, PFKFB3 can also enhance the NF-κB signaling, reduce NLRP3 ubiquitination, and aggravate pyroptosis. However, MET suppressed pyroptosis partly via inhibiting PFKFB3 as well. These results provided that the TLR4/NF-κB/PFKFB3 pathway may be a novel link between metabolism reprogramming and NLRP3 inflammasome-induced pyroptosis in trophoblasts. Further, MET alleviates the NLRP3 inflammasome-induced pyroptosis, which partly relies on the regulation of TLR4/NF-κB/PFKFB3-dependent glycometabolism reprogramming and redox disorders. Hence, our results provide novel insights into the pathogenesis of preeclampsia and propose MET as a potential therapy.

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Exploring Ligand Binding to Calcitonin Gene-Related Peptide Receptors

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.720561 ◽

2021 ◽

Vol 8 ◽

Author(s):

Giuseppe Deganutti ◽

Silvia Atanasio ◽

Roxana-Maria Rujan ◽

Patrick M. Sexton ◽

Denise Wootten ◽

...

Keyword(s):

Molecular Dynamics ◽

Ligand Binding ◽

Calcitonin Gene Related Peptide ◽

Related Peptide ◽

Calcitonin Gene ◽

Approved Drugs ◽

G Protein Coupled ◽

Dynamic Docking ◽

Receptor Family

Class B1 G protein-coupled receptors (GPCRs) are important targets for many diseases, including cancer, diabetes, and heart disease. All the approved drugs for this receptor family are peptides that mimic the endogenous activating hormones. An understanding of how agonists bind and activate class B1 GPCRs is fundamental for the development of therapeutic small molecules. We combined supervised molecular dynamics (SuMD) and classic molecular dynamics (cMD) simulations to study the binding of the calcitonin gene-related peptide (CGRP) to the CGRP receptor (CGRPR). We also evaluated the association and dissociation of the antagonist telcagepant from the extracellular domain (ECD) of CGRPR and the water network perturbation upon binding. This study, which represents the first example of dynamic docking of a class B1 GPCR peptide, delivers insights on several aspects of ligand binding to CGRPR, expanding understanding of the role of the ECD and the receptor-activity modifying protein 1 (RAMP1) on agonist selectivity.

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Discovery of a possible role of asprosin in ovarian follicular function

Journal of Molecular Endocrinology ◽

10.1530/jme-20-0218 ◽

2021 ◽

Vol 66 (1) ◽

pp. 35-44

Author(s):

Excel Rio S Maylem ◽

Leon J Spicer ◽

Isadora Batalha ◽

Luis F Schutz

Keyword(s):

Gene Expression Analysis ◽

Polycystic Ovarian Syndrome ◽

Developmental Regulation ◽

Mrna Abundance ◽

Hormone Regulation ◽

Fibrillin 1 ◽

Ovarian Syndrome ◽

Receptor Family

Asprosin is a novel fasting-induced protein encoded by fibrillin-1 (FBN1) gene, produced when FBN1 is cleaved by the enzyme furin, and is associated with insulin resistance and polycystic ovarian syndrome in humans. To characterize mRNA abundance of FBN1, FURIN, and the presumed asprosin receptor, olfactory receptor family 4 subfamily M member 1 (OR4M1) in granulosa (GC) and theca cells (TC), and identify hormones regulating FBN1 mRNA expression, GC and TC from small (1–5 mm; SM) and large (>8 mm; LG) follicles were collected from ovaries of heifers obtained at an abattoir and used for real-time PCR gene expression analysis or in vitro evaluation of hormone regulation and asprosin effects. SMTC had 151-fold greater (P < 0.05) FBN1 mRNA abundance than SMGC, and LGTC had 50-fold greater FBN1 mRNA than LGGC. In contrast, OR4M1 mRNA was 81-fold greater in SMGC than LGGC and did not differ from SMTC, but LGTC had 9-fold greater OR4M1 mRNA than LGGC. FURIN mRNA was 2.6-fold greater in SMTC than SMGC, but did not differ among follicular sizes. In cultured TC, leptin, insulin, LH, IGF1 and steroids did not affect FBN1 mRNA, but TGFB1 increased (P < 0.05) FBN1 mRNA by 2.2-fold; EGF and FGFs increased FBN1 mRNA by 1.3- to 1.5-fold. Asprosin enhanced LH-induced TC androstenedione production, reduced IGF1-induced TC proliferation, and had no effect on progesterone production. Developmental regulation of FBN1, FURIN and OR4M1 along with direct effects of asprosin on TC suggests that asprosin may be a novel regulator of ovarian follicular function.

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