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Vol. 285, Issue 2, 651-658, May 1998
Department of Pharmacology and Toxicology, Medical College of
Virginia, Virginia Commonwealth University, Richmond, Virginia
The cannabinoid receptors, CB1 and CB2, are members of the G-protein
coupled receptor family and share many of this family's structural
features. A highly conserved aspartic acid residue in the second
transmembrane domain of G-protein coupled receptors has been shown for
many of these receptors to be functionally important for agonist
binding and/or G-protein coupling. To determine whether this residue is
involved in cannabinoid receptor function, we used site-directed
mutagenesis of receptor cDNA followed by expression of the mutant
receptor in HEK 293 cells. Aspartate 163 (in CB1) and aspartate 80 (in
CB2) were substituted with either asparagine or glutamate. Stably
transfected cell lines were tested for radioligand binding and
inhibition of cAMP accumulation. Binding of the cannabinoid receptor
agonist [3H]CP-55,940 was not affected by either mutation
in either the CB1 or CB2 receptor, nor were the affinities of
anandamide or (
)-
9-tetrahydrocannabinol. Binding of
the CB1-selective receptor antagonist SR141716A also was unaltered.
However, the affinity of WIN 55,212-2 was attenuated significantly in
the CB1, but not the CB2, mutant receptors. Studies examining
inhibition of cAMP accumulation showed reduced effects of cannabinoid
agonists in the mutated receptors. Our data suggest that this aspartate
residue is not generally important for ligand recognition in the
cannabinoid receptors; however, it is required for communication with G
proteins and signal transduction.
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