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Vol. 56, Issue 6, 1362-1369, December 1999
Section on Signal Transduction, National Institutes of
Health, National Institute on Deafness and Other Communication
Disorders, Rockville, Maryland
We have examined the ligand regulation and G protein selectivity of the
human cannabinoid CB1 and CB2 receptors by an
in situ reconstitution technique directly measuring G protein
activation. Membranes from Spodoptera frugiperda cells
expressing CB1 and CB2 receptors were chaotrope
extracted to denature endogenous GTP-binding proteins. The ability of
the receptors to catalyze the GDP-GTP exchange of each G protein was
then examined with purified bovine brain Gi and
Go. Activation of CB1 receptors produced a
high-affinity saturable interaction for both Gi and
Go. Agonist stimulation of CB2 receptors also
resulted in a high-affinity saturable interaction with Gi.
In contrast, CB2 receptors did not interact efficiently
with Go. G protein activation was then examined with a
diverse group of ligands. For the interaction of CB2
receptors with Gi, HU210 was the only compound tested that demonstrated maximal activation. In contrast, WIN55,212 (64%), anandamide (42%), and 
9-tetrahydrocannabinol
(9-THC) (44%) all initiated submaximal levels of G
protein activation. For CB1 receptor-catalyzed activation
of Gi, HU210, WIN55,212, and anandamide all elicited
maximal activation, whereas 9-THC (56 ± 6%)
caused only partial Gi activation. In contrast, only HU210
effected maximal CB1 stimulation of Go, with
anandamide, WIN55,212, and 9-THC all stimulating between
60 and 75% compared with HU210. These data demonstrate that different
agonists induce different conformations of the CB1
receptor, which in turn can distinguish between different G proteins.
Our data thus demonstrate agonist-selective G protein signaling by the
CB1 receptor and suggest that therapeutic agents may be
designed to regulate individual G protein-signaling pathways selectively.
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