Article date: June 2004
By: Terry Luk, Wenzhen Jin, Alexander Zvonok, Dai Lu, Xin‐Zhong Lin, Charles Chavkin, Alexandros Makriyannis, Ken Mackie in Volume 142, Issue 3, pages 495-500
The relationship of agonist efficacy to the rate of G protein‐coupled receptor signaling desensitization is controversial.
Expressing inwardly rectifying potassium channels (GIRKs) in Xenopus oocytes, we have devised a signaling assay that clearly identifies CB1 cannabinoid receptor agonists with low intrinsic efficacy.
In this assay, the synthetic CB1 agonists, AM411, AM782, AM1902, AM2233 and WIN55,212‐2 and the endogenous cannabinoid, 2‐arachidonoyl ester, were full agonists.
The synthetic CB1 agonist AM356 (methanandamide), the endogenous cannabinoids, anandamide and 2‐arachidonoyl ether, and the phytocannabinoid, Δ9THC, were partial agonists.
The rate of desensitization of CB1 was independent of agonist efficacy. WIN55,212‐2, AM782, AM1902, AM2233, and 2‐arachidonoyl glycerol ester all desensitized quickly, with desensitization rates varying from 14% min−1 to 10% min−1. AM356, AM411, anandamide, and Δ9THC all desensitized considerably slower, at a rate of 5% min−1.
Despite high potency and efficacy, AM411 desensitized as slowly as anandamide and Δ9THC.
CB1 agonist efficacy and rate of desensitization are not necessarily related.
The relationship of agonist efficacy to the rate of G protein‐coupled receptor signaling desensitization is controversial.
Expressing inwardly rectifying potassium channels (GIRKs) in Xenopus oocytes, we have devised a signaling assay that clearly identifies CB1 cannabinoid receptor agonists with low intrinsic efficacy.
In this assay, the synthetic CB1 agonists, AM411, AM782, AM1902, AM2233 and WIN55,212‐2 and the endogenous cannabinoid, 2‐arachidonoyl ester, were full agonists.
The synthetic CB1 agonist AM356 (methanandamide), the endogenous cannabinoids, anandamide and 2‐arachidonoyl ether, and the phytocannabinoid, Δ9THC, were partial agonists.
The rate of desensitization of CB1 was independent of agonist efficacy. WIN55,212‐2, AM782, AM1902, AM2233, and 2‐arachidonoyl glycerol ester all desensitized quickly, with desensitization rates varying from 14% min−1 to 10% min−1. AM356, AM411, anandamide, and Δ9THC all desensitized considerably slower, at a rate of 5% min−1.
Despite high potency and efficacy, AM411 desensitized as slowly as anandamide and Δ9THC.
CB1 agonist efficacy and rate of desensitization are not necessarily related.
British Journal of Pharmacology (2004) 142, 495–500. doi:10.1038/sj.bjp.0705792
DOI: 10.1038/sj.bjp.0705792
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