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Vol. 54, Issue 6, 1064-1072, December 1998
Department of Pharmacology and Toxicology, Medical College of
Georgia, Augusta, Georgia 30912-2300
The CB1 cannabinoid receptor antagonist SR 141716A abolished the
inhibition of Ca2+ currents by the agonist WIN 55,212-2.
However, SR 141716A alone increased Ca2+ currents, with an
EC50 of 32 nM, in neurons that had been
microinjected with CB1 cRNA. For an antagonist to elicit an effect,
some receptors must be tonically active. Evidence for tonically active
CB1 receptors was seen as enhanced tonic inhibition of Ca2+
currents. Preincubation with anandamide failed to enhance the effect of
SR 141716A, indicating that anandamide did not cause receptor activity.
Under Ca2+-free conditions designed to block the
Ca2+-dependent formation of anandamide and
sn-2-arachidonylglycerol, SR 141716A again increased the
Ca2+ current. The Ca2+ current was tonically
inhibited in neurons expressing the mutant K192A receptor, which has no
affinity for anandamide, demonstrating that this receptor is also
tonically active. SR 141716A had no effect on the Ca2+
current in these neurons, but SR 141716A could still antagonize the
effect of WIN 55,212-2. Thus, the K192 site is critical for the
inverse agonist activity of SR 141716A. SR 141716A appeared to become a
neutral antagonist at the K192A mutant receptor. Native cannabinoid
receptors were studied in male rat major pelvic ganglion neurons, where
it was found that WIN 55,212-2 inhibited and SR 141716A increased
Ca2+ currents. Taken together, our results demonstrate that
a population of native and cloned CB1 cannabinoid receptors can exist
in a tonically active state that can be reversed by SR 141716A, which acts as an inverse agonist.
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