Document Detail


The stimulation of ketogenesis by cannabinoids in cultured astrocytes defines carnitine palmitoyltransferase I as a new ceramide-activated enzyme.
MedLine Citation:
PMID:  10098887     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The effects of cannabinoids on ketogenesis in primary cultures of rat astrocytes were studied. Delta9-Tetrahydrocannabinol (THC), the major active component of marijuana, produced a malonyl-CoA-independent stimulation of carnitine palmitoyltransferase I (CPT-I) and ketogenesis from [14C]palmitate. The THC-induced stimulation of ketogenesis was mimicked by the synthetic cannabinoid HU-210 and was prevented by pertussis toxin and the CB1 cannabinoid receptor antagonist SR141716. Experiments performed with different cellular modulators indicated that the THC-induced stimulation of ketogenesis was independent of cyclic AMP, Ca2+, protein kinase C, and mitogen-activated protein kinase (MAPK). The possible involvement of ceramide in the activation of ketogenesis by cannabinoids was subsequently studied. THC produced a CB1 receptor-dependent stimulation of sphingomyelin breakdown that was concomitant to an elevation of intracellular ceramide levels. Addition of exogenous sphingomyelinase to the astrocyte culture medium led to a MAPK-independent activation of ketogenesis that was quantitatively similar and not additive to that exerted by THC. Furthermore, ceramide activated CPT-I in astrocyte mitochondria. Results thus indicate that cannabinoids stimulate ketogenesis in astrocytes by a mechanism that may rely on CB1 receptor activation, sphingomyelin hydrolysis, and ceramide-mediated activation of CPT-I.
Authors:
C Blázquez; C Sánchez; A Daza; I Galve-Roperh; M Guzmán
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of neurochemistry     Volume:  72     ISSN:  0022-3042     ISO Abbreviation:  J. Neurochem.     Publication Date:  1999 Apr 
Date Detail:
Created Date:  1999-04-13     Completed Date:  1999-04-13     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1759-68     Citation Subset:  IM    
Affiliation:
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.
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MeSH Terms
Descriptor/Qualifier:
Animals
Astrocytes / cytology,  drug effects,  enzymology*
Calcium / metabolism
Calcium-Calmodulin-Dependent Protein Kinases / metabolism
Carnitine O-Palmitoyltransferase / metabolism*
Cells, Cultured
Cerebral Cortex / cytology
Cyclic AMP / metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Ketone Bodies / metabolism*
Malonyl Coenzyme A / metabolism
Mitochondria / enzymology
Piperidines / pharmacology
Protein Kinase C / metabolism
Psychotropic Drugs / pharmacology*
Pyrazoles / pharmacology
Rats
Receptors, Cannabinoid
Receptors, Drug / metabolism
Sphingomyelin Phosphodiesterase / pharmacology
Sphingomyelins / metabolism*
Sphingosine / analogs & derivatives,  pharmacology
Tetrahydrocannabinol / pharmacology*
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Ketone Bodies; 0/N-acetylsphingosine; 0/Piperidines; 0/Psychotropic Drugs; 0/Pyrazoles; 0/Receptors, Cannabinoid; 0/Receptors, Drug; 0/Sphingomyelins; 123-78-4/Sphingosine; 158681-13-1/rimonabant; 1972-08-3/Tetrahydrocannabinol; 524-14-1/Malonyl Coenzyme A; 60-92-4/Cyclic AMP; 7440-70-2/Calcium; EC 2.3.1.21/Carnitine O-Palmitoyltransferase; EC 2.7.11.13/Protein Kinase C; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinases; EC 3.1.4.12/Sphingomyelin Phosphodiesterase

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