2-Arachidonoylglycerol, a Putative Endogenous Cannabinoid Receptor Ligand, Induces Rapid, Transient Elevation of Intracellular Free Ca2+in Neuroblastoma × Glioma Hybrid NG108-15 Cells

Sugiura, Takayuki; Kodaka, Tomoko; Kondo, Sachiko; Tonegawa, Takashi; Nakane, Shinji; Kishimoto, Seishi; Yamashita, Atsushi; Waku, Keizo

doi:10.1006/bbrc.1996.1757

Cited by 161 publications

(128 citation statements)

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“…To confirm the functional antagonistic activities of MJ08 toward the cannabinoid CB 1 [20] . In our experiment, similar to SR141716A and other reported antagonists [23,24] ] i and cAMP assays demonstrated that MJ08 acts as a cannabinoid CB 1 receptor antagonist of second messenger signaling in mammalian cells with similar efficacy to SR141716A. Additionally, both SR141716A and MJ08 significantly antagonized the inhibition by WIN 55,212-2 of the contraction of mouse vas deferens smooth muscle with electrical stimulation.…”

Section: Discussionsupporting

confidence: 86%

Novel selective cannabinoid CB1 receptor antagonist MJ08 with potent in vivo bioactivity and inverse agonistic effects

Chen¹,

Liu³

et al. 2011

Acta Pharmacol Sin

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Aim: To characterize the biological profiles of MJ08, a novel selective CB 1 receptor antagonist. Methods: Radioligand binding assays were performed using rat brain and spleen membrane preparations. CB 1 and CB 2 receptor redistribution and intracellular Ca 2+ ([Ca 2+ ] i ) assays were performed with IN CELL Analyzer. Inverse agonism was studied using intracellular cAMP assays, and in guinea-pig ileum and mouse vas deferens smooth muscle preparations. In vivo pharmacologic profile was assessed in diet-induced obesity (DIO) mice. Results: In radioligand binding assay, MJ08 selectively antagonized CB 1 receptor (IC 50 =99.9 nmol/L). In EGFP-CB 1 _U2OS cells, its IC 50 value against CB 1 receptor activation was 30.23 nmol/L (SR141716A: 32.16 nmol/L). WIN 55,212-2 (1 μmol/L) increased [Ca 2+ ] i in the primary cultured hippocampal neuronal cells and decreased cAMP accumulation in CHO-hCB 1 cells. MJ08 (10 nmol/L-10 μmol/L) blocked both the WIN 55,212-2-induced effects. Furthermore, MJ08 reversed the inhibition of electrically evoked twitches of mouse vas deferens by WIN 55,212-2 (pA 2 =10.29±1.05). MJ08 and SR141716A both showed an inverse agonism activity by markedly promoting the contraction force and frequency of guinea pig ileum muscle. MJ08 significantly increased the cAMP level in CHO-hCB 1 cells with an EC 50 value of 78.6 nmol/L, which was lower than the EC 50 value for SR141716A (159.2 nmol/L). Besides the more potent pharmacological effects of cannabinoid CB 1 receptor antagonism in DIO mice, such as reducing food intake, decreasing body weight, and ameliorating dyslipidemia, MJ08 (10 mg/kg) unexpectedly raised the fasted blood glucose in vivo. Conclusion: MJ08 is a novel, potent and selective CB 1 receptor antagonist/inverse agonist with potent bioactive responses in vitro and in vivo that may be useful for disclosure the versatile nature of CB 1 receptors.

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Section: Discussionsupporting

confidence: 86%

Novel selective cannabinoid CB1 receptor antagonist MJ08 with potent in vivo bioactivity and inverse agonistic effects

Chen¹,

Liu³

et al. 2011

Acta Pharmacol Sin

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“…Our (Howlett, 2005), the majority of these studies identified the involvement of G i/o proteins, which are capable of mobilizing Ca 2 þ via bg-subunit activation of PLC (Sugiura et al, 1996;Netzeband et al, 1999;Rubovitch et al, 2004 In hTM cells, WIN55,212-2 activation of endogenous CB 1 -G q/11 signalling involved activation of PLC and mobilization of Ca 2 þ from thapsigargin and cyclopiazonic acid-sensitive intracellular stores. The possibility of WIN55,212-2 increasing Ca 2 þ in hTM cells through direct inhibition of the sarcoplasmic/endoplasmic reticulum Ca 2 þ ATPase pumps is unlikely as hTM cells were still able to respond to 10 mM ATP with an increase in Ca 2 þ following exposure to WIN55,212-2 (data not shown), a process that is known to require intact Ca 2 þ stores (von Kügelgen and Wetter, 2000).…”

Section: Discussionmentioning

confidence: 91%

Agonist‐dependent cannabinoid receptor signalling in human trabecular meshwork cells

McIntosh

Hudson

Yegorova

et al. 2007

British J Pharmacology

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Background and purpose: Trabecular meshwork (TM) is an ocular tissue involved in the regulation of aqueous humour outflow and intraocular pressure (IOP). CB 1 receptors (CB 1 ) are present in TM and cannabinoid administration decreases IOP. CB 1 signalling was investigated in a cell line derived from human TM (hTM). Experimental approach: CB 1 signalling was investigated using ratiometric Ca 2 þ imaging, western blotting and infrared In-Cell Western analysis. Key results: WIN55212-2, a synthetic aminoalkylindole cannabinoid receptor agonist (10-100 mM) increased intracellular Ca 2 þ in hTM cells. WIN55,212-2-mediated Ca 2 þ increases were blocked by AM251, a CB 1 antagonist, but were unaffected by the CB 2 antagonist, AM630. The WIN55,212-2-mediated increase in [Ca 2 þ ] i was pertussis toxin (PTX)-insensitive, therefore, independent of G i/o coupling, but was attenuated by a dominant negative Ga q/11 subunit, implicating a G q/11 signalling pathway. The increase in [Ca 2 þ ] i was dependent upon PLC activation and mobilization of intracellular Ca 2 þ stores. A PTXsensitive increase in extracellular signal-regulated kinase (ERK1/2) phosphorylation was also observed in response to WIN55,212-2, indicative of a G i/o signalling pathway. CB 1 -G q/11 coupling to activate PLC-dependent increases in Ca 2 þ appeared to be specific to WIN55,212-2 and were not observed with other CB 1 agonists, including CP55,940 and methanandamide. CP55940 produced PTX-sensitive increases in [Ca 2 þ ] i at concentrations Z15 mM, and PTX-sensitive increases in ERK1/2 phosphorylation. Conclusions and implications: This study demonstrates that endogenous CB 1 couples to both G q/11 and G i/o in hTM cells in an agonist-dependent manner. Cannabinoid activation of multiple CB 1 signalling pathways in TM tissue could lead to differential changes in aqueous humour outflow and IOP.

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“…CB 1 R stimulation leads to an increase in Ca 2C levels in N18TG and NG108-15 cells, but not in C9 cells (Sugiura et al 1996). It has also been reported that this response was pertussis toxin-sensitive in NG108-15 cells, suggesting the role of G i/o proteins, which can regulate b2 isoform of phospholipase C (PLC) via Gbg subunits, in this response (Sugiura et al 1996(Sugiura et al , 1997. In contrast, in HEK cells expressing CB 1 R, only WIN55 212-2 caused Ca 2C signal generation, which occurred through activation of G q proteins (Lauckner et al 2005).…”

Section: Stimulation Of Camp Productionmentioning

confidence: 85%

“…1A), however, the mechanism of this response is not clear. CB 1 R stimulation leads to an increase in Ca 2C levels in N18TG and NG108-15 cells, but not in C9 cells (Sugiura et al 1996). It has also been reported that this response was pertussis toxin-sensitive in NG108-15 cells, suggesting the role of G i/o proteins, which can regulate b2 isoform of phospholipase C (PLC) via Gbg subunits, in this response (Sugiura et al 1996(Sugiura et al , 1997.…”

Section: Stimulation Of Camp Productionmentioning

confidence: 97%

Signal transduction of the CB1 cannabinoid receptor

Turu

Hunyady

2009

Journal of Molecular Endocrinology

281

218

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The CB 1 cannabinoid receptor (CB 1 R) is the major cannabinoid receptor in neuronal cells and the brain, but it also occurs in endocrine cells and other peripheral tissues. CB 1 R is a member of the superfamily of G-protein-coupled receptors (GPCRs), which are characterized by seven transmembrane helices. The major mediators of CB 1 R are the G proteins of the G i/o family, which inhibit adenylyl cyclases in most tissues and cells, and regulate ion channels, including calcium and potassium ion channels. Regulation of ion channels is an important component of neurotransmission modulation by endogenous cannabinoid compounds released in response to depolarization and Ca 2C -mobilizing hormones. However, evidence exists that CB 1 Rs can also stimulate adenylyl cyclase via G s , induce receptor-mediated Ca 2C fluxes and stimulate phospholipases in some experimental models. Stimulation of CB 1 R also leads to phosphorylation and activation of mitogen-activated protein kinases (MAPK), such as p42/p44 MAPK, p38 MAPK and c-Jun N-terminal kinase, which can regulate nuclear transcription factors. Activated and phosphorylated CB 1 Rs also associate with b-arrestin molecules, which can induce the formation of signalling complexes and participate in the regulation of GPCR signalling. Recent data also suggest that CB 1 Rs can form homo-and heterodimers/oligomers, and the altered pharmacological properties of these receptor complexes may explain the pharmacological differences observed in various tissues.

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2-Arachidonoylglycerol, a Putative Endogenous Cannabinoid Receptor Ligand, Induces Rapid, Transient Elevation of Intracellular Free Ca2+in Neuroblastoma × Glioma Hybrid NG108-15 Cells

Cited by 161 publications

References 0 publications

Novel selective cannabinoid CB1 receptor antagonist MJ08 with potent in vivo bioactivity and inverse agonistic effects

Novel selective cannabinoid CB1 receptor antagonist MJ08 with potent in vivo bioactivity and inverse agonistic effects

Agonist‐dependent cannabinoid receptor signalling in human trabecular meshwork cells

Signal transduction of the CB1 cannabinoid receptor

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