Involvement of sphingomyelin hydrolysis and the mitogen-activated protein kinase cascade in the Delta9-tetrahydrocannabinol-induced stimulation of glucose metabolism in primary astrocytes.
The effects of cannabinoids on metabolic pathways and signal transduction systems were studied in primary cultures of rat astrocytes. Delta9-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 analog D-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.
Sánchez
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C
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, 28040-Madrid, Spain.
Galve-Roperh
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I
Rueda
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D
Guzmán
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M
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D013759:Dronabinol / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006868:Hydrolysis; D010766:Phosphorylation; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism / Q000494:pharmacology; D013109:Sphingomyelins / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D013268:Stimulation, Chemical
C066099:2,3-N-octanoylsphingosine; D004791:Enzyme Inhibitors; D005419:Flavonoids; D013109:Sphingomyelins; D013759:Dronabinol; D000242:Cyclic AMP; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D013108:Sphingomyelin Phosphodiesterase; D005947:Glucose; D013110:Sphingosine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one