The CB(1) cannabinoid receptor of astrocytes is coupled to sphingomyelin hydrolysis through the adaptor protein fan.
Cannabinoids exert most of their effects through the CB(1) receptor. This G protein-coupled receptor signals inhibition of adenylyl cyclase, modulation of ion channels, and stimulation of mitogen- and stress-activated protein kinases. In this article, we report that Delta(9)-tetrahydrocannabinol (THC), the major active component of marijuana, induces sphingomyelin hydrolysis in primary astrocytes but not in other cells expressing the CB(1) receptor, such as primary neurons, U373 MG astrocytoma cells, and Chinese hamster ovary cells transfected with the CB(1) receptor cDNA. THC-evoked sphingomyelin breakdown in astrocytes was also exerted by the endogenous cannabinoid anandamide and the synthetic cannabinoid HU-210 and was prevented by the selective CB(1) antagonist SR141716. By contrast, the effect of THC was not blocked by pertussis toxin, pointing to a lack of involvement of G(i/o) proteins. A role for the adaptor protein FAN in CB(1) receptor-coupled sphingomyelin breakdown is supported by two observations: 1) coimmunoprecipitation experiments show that the binding of FAN to the CB(1) receptor is enhanced by THC and prevented by SR141716; 2) cells expressing a dominant-negative form of FAN are refractory to THC-induced sphingomyelin breakdown. This is the first report showing that a G-protein-coupled receptor induces sphingomyelin hydrolysis through FAN and that the CB(1) cannabinoid receptor may signal independently of G(i/o) proteins.
Sánchez
C
C
Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University, Madrid, Spain.
Rueda
D
D
Ségui
B
B
Galve-Roperh
I
I
Levade
T
T
Guzmán
M
M
D037361:Adenylate Cyclase Toxin; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002186:Cannabinoids / Q000378:metabolism; D002478:Cells, Cultured; D006868:Hydrolysis; D047908:Intracellular Signaling Peptides and Proteins; D037342:Pertussis Toxin; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism*; D013109:Sphingomyelins / Q000378:metabolism*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D002186:Cannabinoids; D047908:Intracellular Signaling Peptides and Proteins; C491113:Nsmaf protein, rat; D011506:Proteins; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013109:Sphingomyelins; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin