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Vol. 57, Issue 5, 1045-1050, May 2000
Department of Immunology, Schering-Plough Research Institute,
Kenilworth, New Jersey
The endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG) bind
to G protein-coupled central and peripheral cannabinoid receptors CB1
and CB2, respectively. Due to the relatively high expression of the CB2
isotype on peripheral immune cells, it has been hypothesized that this
receptor mediates the immunosuppressive effects of cannabinoids.
Unfortunately, there was a dearth of pharmacological studies with the
endocannabinoids and human CB2 (hCB2). These studies compare and
contrast the potency and efficacy of anandamide, 2-AG, and the
synthetic cannabinoid HU210 at hCB2. Using
[35S]guanosine-5'-O-(3-thio)triphosphate
(GTP
S) and radioligand bindings in insect Sf9-hCB2 membranes, we
showed that both endocannabinoids bound hCB2 with similar affinity and
that the cannabinoids acted as full agonists in stimulating
[35S]GTPS exchange, although 2-AG was 3-fold more
potent than anandamide (EC50 = 38.9 ± 3.1 and
121 ± 29 nM, respectively). In a mammalian expression system
(Chinese hamster ovary-hCB2 cells), HU210 and 2-AG maximally inhibited
forskolin-stimulated cAMP synthesis (IC50 = 1.61 ± 0.42 nM and 1.30 ± 0.37 µM, respectively) although anandamide was ineffective. In Chinese hamster ovary-hCB2 membranes, HU210 and
2-AG were also full agonists in stimulating [35S]GTPS
binding (EC50 = 1.96 ± 0.35 and 122 ± 17 nM,
respectively), but anandamide was a weak partial agonist
(EC50 = 261 ± 91 nM; 34 ± 4% of maximum).
Due to its low intrinsic activity, coincubation with anandamide
effectively attenuated the functional activity of 2-AG at hCB2.
Collectively, the data showed that both endocannabinoids bound hCB2
with similar affinity, but only 2-AG functioned as a full agonist.
Moreover, the agonistic activity of 2-AG was attenuated by anandamide.
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