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Vol. 291, Issue 2, 618-626, November 1999
Department of Pharmacology and Toxicology, Medical College
of Virginia Campus of Virginia Commonwealth University, Richmond,
Virginia
In this study, we focused on the pharmacological characterization of
cannabinoid receptor coupling to G protein-gated inwardly rectifying
potassium (GIRK) channels. Cannabinoids were tested on Xenopus
laevis oocytes coexpressing the CB1 receptor and
GIRK1 and GIRK4 channels (CB1/GIRK1/4) or the
CB2 receptor and GIRK1/4 channels
(CB2/GIRK1/4). WIN 55,212-2 enhanced currents carried by
GIRK channels in the CB1/GIRK1/4 and
CB2/GIRK1/4 system; however, the CB2 receptor
did not couple efficiently to GIRK1/4 channels. In the
CB1/GIRK1/4 system, WIN 55,212-2 was the most efficacious compound tested. CP 55,940 and anandamide acted as partial agonists. The rank order of potency was CP 55,940 > WIN 55,212-2 = anandamide. The CB1-selective antagonist SR141716A alone
acted as a inverse agonist by inhibiting GIRK currents in oocytes
expressing CB1/GIRK1/4, suggesting the CB1
receptor is constitutively activated. A conserved aspartate residue,
which was previously shown to be critical for G protein coupling in
cannabinoid receptors, was mutated (to asparagine, D163N) and analyzed.
Oocytes coexpressing CB1/GIRK1/4 or D163N/GIRK1/4 were
compared. The potency of WIN 55,212-2 at the mutant receptor was
similar to wild type, but its efficacy was substantially reduced. CP
55,940 did not elicit currents in oocytes expressing D163N/GIRK1/4. In
summary, it appears the CB1 and CB2 receptors
couple differently to GIRK1/4 channels. In the CB1/GIRK1/4
system, cannabinoids evaluated demonstrated the ability to enhance or
inhibit GIRK currents. Furthermore, a conserved aspartate residue in
the CB1 receptor is required for normal communication with
GIRK channels in oocytes demonstrating the interaction between receptor
and channels is G protein dependent.
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