Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You and Your Team.

Learn More →

Despite substantial degradation, 2‐arachidonoylglycerol is a potent full efficacy agonist mediating CB 1 receptor‐dependent G‐protein activation in rat cerebellar membranes

Despite substantial degradation, 2‐arachidonoylglycerol is a potent full efficacy agonist... Two endocannabinoids, arachidonoyl ethanolamide (AEA) and 2‐arachidonoylglycerol (2‐AG) bind and activate G‐protein‐coupled cannabinoid receptors, but limited data exist on their relative ability to activate G‐proteins. Here we assess agonist potency and efficacy of various cannabinoids, including 2‐AG, HU‐310 (2‐arachidonoyl glyceryl ether, a third putative endocannabinoid), HU‐313 (another ether analogue of 2‐AG), AEA, R‐methanandamide (an enzymatically stable analogue of AEA), and CP‐55,940 at rat brain CB1 receptors using agonist‐stimulated (35S)‐GTPγS binding to cerebellar membranes and whole brain sections. Degradation of endocannabinoids under experimental conditions was monitored by HPLC. To enhance efficacy differences, agonist dose‐response curves were generated using increasing GDP concentrations. At 10−6 M GDP, all compounds, except HU‐313, produced full agonists responses ∼2.5 fold over basal. The superior efficacy of 2‐AG over all other compounds became evident by increasing GDP (10−5 and 10−4 M). In membrane incubations, 2‐AG was degraded by 85% whereas AEA and HU‐310 were stable. Pretreatment of membranes with phenylmethylsulphonyl fluoride inhibited 2‐AG degradation, resulting in 2 fold increase in agonist potency. Such pretreatment had no effect on AEA potency. Responses in brain sections were otherwise consistent with membrane binding data, but 2‐AG evoked only a weak signal in brain sections, apparently due to more extensive degradation. These data establish that even under conditions of substantial degradation, 2‐AG is a full efficacy agonist, clearly more potent than AEA, in mediating CB1 receptor‐dependent G‐protein activity in native membranes. British Journal of Pharmacology (2001) 134, 664–672; doi:10.1038/sj.bjp.0704297 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Despite substantial degradation, 2‐arachidonoylglycerol is a potent full efficacy agonist mediating CB 1 receptor‐dependent G‐protein activation in rat cerebellar membranes

Loading next page...
 
/lp/wiley/despite-substantial-degradation-2-arachidonoylglycerol-is-a-potent-HdjlWNFgL0
Publisher
Wiley
Copyright
2001 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1038/sj.bjp.0704297
pmid
11588122
Publisher site
See Article on Publisher Site

Abstract

Two endocannabinoids, arachidonoyl ethanolamide (AEA) and 2‐arachidonoylglycerol (2‐AG) bind and activate G‐protein‐coupled cannabinoid receptors, but limited data exist on their relative ability to activate G‐proteins. Here we assess agonist potency and efficacy of various cannabinoids, including 2‐AG, HU‐310 (2‐arachidonoyl glyceryl ether, a third putative endocannabinoid), HU‐313 (another ether analogue of 2‐AG), AEA, R‐methanandamide (an enzymatically stable analogue of AEA), and CP‐55,940 at rat brain CB1 receptors using agonist‐stimulated (35S)‐GTPγS binding to cerebellar membranes and whole brain sections. Degradation of endocannabinoids under experimental conditions was monitored by HPLC. To enhance efficacy differences, agonist dose‐response curves were generated using increasing GDP concentrations. At 10−6 M GDP, all compounds, except HU‐313, produced full agonists responses ∼2.5 fold over basal. The superior efficacy of 2‐AG over all other compounds became evident by increasing GDP (10−5 and 10−4 M). In membrane incubations, 2‐AG was degraded by 85% whereas AEA and HU‐310 were stable. Pretreatment of membranes with phenylmethylsulphonyl fluoride inhibited 2‐AG degradation, resulting in 2 fold increase in agonist potency. Such pretreatment had no effect on AEA potency. Responses in brain sections were otherwise consistent with membrane binding data, but 2‐AG evoked only a weak signal in brain sections, apparently due to more extensive degradation. These data establish that even under conditions of substantial degradation, 2‐AG is a full efficacy agonist, clearly more potent than AEA, in mediating CB1 receptor‐dependent G‐protein activity in native membranes. British Journal of Pharmacology (2001) 134, 664–672; doi:10.1038/sj.bjp.0704297

Journal

British Journal of PharmacologyWiley

Published: Oct 1, 2001

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$499/year

Save searches from
Google Scholar,
PubMed

Create folders to
organize your research

Export folders, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month