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Molecular Pharmacology

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Research ArticleArticle

Involvement of Sphingomyelin Hydrolysis and the Mitogen-Activated Protein Kinase Cascade in the Δ9-Tetrahydrocannabinol-Induced Stimulation of Glucose Metabolism in Primary Astrocytes

Cristina Sánchez, Ismael Galve-Roperh, Daniel Rueda and Manuel Guzmán
Molecular Pharmacology November 1998, 54 (5) 834-843; DOI: https://doi.org/10.1124/mol.54.5.834
Cristina Sánchez
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040-Madrid, Spain
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Ismael Galve-Roperh
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040-Madrid, Spain
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Daniel Rueda
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040-Madrid, Spain
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Manuel Guzmán
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040-Madrid, Spain
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Abstract

The effects of cannabinoids on metabolic pathways and signal transduction systems were studied in primary cultures of rat astrocytes. Δ9-Tetrahydrocannabinol (THC), the major active component of marijuana, increased the rate of glucose oxidation to CO2 as well as the rate of glucose incorporation into phospholipids and glycogen. These effects of THC were mimicked by the synthetic cannabinoid HU-210, and prevented by forskolin, pertussis toxin, and the CB1 receptor antagonist SR 141716. THC did not affect basal cAMP levels but partially antagonized the forskolin-induced elevation of intracellular cAMP concentration. THC stimulated p42/p44 mitogen-activated protein kinase (MAPK) activity, Raf-1 phosphorylation, and Raf-1 translocation to the particulate cell fraction. In addition, the MAPK inhibitor PD 098095 and the phosphoinositide 3-kinase inhibitors wortmannin and LY 294002 were able to antagonize the THC-induced stimulation of glucose oxidation to CO2, phospholipid synthesis and glycogen synthesis. The possible involvement of sphingomyelin breakdown in the metabolic effects of THC was studied subsequently. THC produced a rapid stimulation of sphingomyelin hydrolysis that was concomitant to an elevation of intracellular ceramide levels. This effect was prevented by SR 141716. Moreover, the cell-permeable ceramide analogd-erythro-N-octanoylsphingosine, as well as exogenous sphingomyelinase, were able in turn to stimulate MAPK activity, to increase the amount of Raf-1 bound to the particulate cell fraction, and to stimulate glucose metabolism. The latter effect was prevented by PD 098059 and was not additive to that exerted by THC. Results thus indicate that THC produces a cannabinoid receptor-mediated stimulation of astrocyte metabolism that seems to rely on sphingomyelin hydrolysis and MAPK stimulation.

Footnotes

    • Received March 9, 1998.
    • Accepted August 20, 1998.
  • Send reprint requests to: Dr. Manuel Guzmán, Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040-Madrid, Spain. E-mail:mgp{at}solea.quim.ucm.es

  • This study was supported by grants from Comisión Interministerial de Ciencia y Tecnologı́a (SAF 96/0113), Fondo de Investigación Sanitaria (FIS 97/0039) and Comunidad Autónoma de Madrid (CAM-6648).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (5)
Molecular Pharmacology
Vol. 54, Issue 5
1 Nov 1998
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Research ArticleArticle

Involvement of Sphingomyelin Hydrolysis and the Mitogen-Activated Protein Kinase Cascade in the Δ9-Tetrahydrocannabinol-Induced Stimulation of Glucose Metabolism in Primary Astrocytes

Cristina Sánchez, Ismael Galve-Roperh, Daniel Rueda and Manuel Guzmán
Molecular Pharmacology November 1, 1998, 54 (5) 834-843; DOI: https://doi.org/10.1124/mol.54.5.834

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Research ArticleArticle

Involvement of Sphingomyelin Hydrolysis and the Mitogen-Activated Protein Kinase Cascade in the Δ9-Tetrahydrocannabinol-Induced Stimulation of Glucose Metabolism in Primary Astrocytes

Cristina Sánchez, Ismael Galve-Roperh, Daniel Rueda and Manuel Guzmán
Molecular Pharmacology November 1, 1998, 54 (5) 834-843; DOI: https://doi.org/10.1124/mol.54.5.834
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