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Vol. 59, Issue 5, 955-959, May 2001
Department of Biochemistry and Molecular Biology I, School of
Biology, Complutense University, Madrid, Spain (C.S., D.R., I.G.-R.,
M.G.); and Institut National de la Santé et de la Recherche
Médicale U466, Laboratoire de Biochimie, Centre Hospitalier
Universitaire Rangeil, Toulouse, France (B.S., T.L.)
Cannabinoids exert most of their effects through the
CB1 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 
9-tetrahydrocannabinol (THC),
the major active component of marijuana, induces sphingomyelin
hydrolysis in primary astrocytes but not in other cells expressing the
CB1 receptor, such as primary neurons, U373 MG astrocytoma
cells, and Chinese hamster ovary cells transfected with the
CB1 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
CB1 antagonist SR141716. By contrast, the effect of THC was
not blocked by pertussis toxin, pointing to a lack of involvement of
Gi/o proteins. A role for the adaptor protein FAN in
CB1 receptor-coupled sphingomyelin breakdown is supported
by two observations: 1) coimmunoprecipitation experiments show that the
binding of FAN to the CB1 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 CB1 cannabinoid receptor may signal independently of Gi/o proteins.
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