C. Sanchez et al., The CB1 cannabinoid receptor of astrocytes is coupled to sphingomyelin hydrolysis through the adaptor protein fan, MOLEC PHARM, 59(5), 2001, pp. 955-959
Cannabinoids exert most of their effects through the CB1 receptor. This G p
rotein-coupled receptor signals inhibition of adenylyl cyclase, modulation
of ion channels, and stimulation of mitogen- and stress-activated protein k
inases. In this article, we report that Delta (9)-tetrahydrocannabinol (THC
), the major active component of marijuana, induces sphingomyelin hydrolysi
s in primary astrocytes but not in other cells expressing the CB1 receptor,
such as primary neurons, U373 MG astrocytoma cells, and Chinese hamster ov
ary cells transfected with the CB1 receptor cDNA. THC-evoked sphingomyelin
breakdown in astrocytes was also exerted by the endogenous cannabinoid anan
damide and the synthetic cannabinoid HU-210 and was prevented by the select
ive CB1 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 CB1 receptor-coupled sphingomyelin br
eakdown is supported by two observations: 1) coimmunoprecipitation experime
nts 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 r
eport showing that a G-protein-coupled receptor induces sphingomyelin hydro
lysis through FAN and that the CB1 cannabinoid receptor may signal independ
ently of G(i/o) proteins.