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J Recept Signal Transduct Res. 2013 Dec;33(6):367-79. doi: 10.3109/10799893.2013.838787. Epub 2013 Oct 4.

The influence of beta-arrestin2 on cannabinoid CB1 receptor coupling to G-proteins and subcellular localization and relative levels of beta-arrestin1 and 2 in mouse brain.

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  • 1Department of Pharmaceutical Sciences, Campbell University College of Pharmacy & Health Sciences , NC , USA .

Abstract

CONTEXT:

Beta-arrestins are known to couple to some G-protein-coupled receptors (GPCRs) to regulate receptor internalization, G-protein coupling and signal transduction, but have not been investigated for most receptors, and for very few receptors in vivo. Previous studies have shown that beta-arrestin2 deletion enhances the efficacy of specific cannabinoid agonists.

OBJECTIVE:

The present study hypothesized that brain cannabinoid CB1 receptors are regulated by beta-arrestin2.

METHODS:

Beta-arrestin2+/+ and -/- mice were used. Western blotting was used to determine the relative levels of each beta-arrestin subtype in mouse brain. Receptor binding was measured to determine whether deletion of beta-arrestin2 influences agonist binding to brain CB1 receptors, or the subcellular localization of CB1 in brain membranes subjected to differential centrifugation. A variety of cannabinoid agonists from different chemical classes were investigated for their ability to activate G-proteins in the presence and absence of beta-arrestin2 in cerebellum, hippocampus and cortex.

RESULTS:

No differences were found in the density of beta-arrestin1 or cannabinoid CB1 receptors in several brains of beta-arrestin2+/+ versus -/- mice. Differences between genotypes were found in the proportion of high- and low-affinity agonist binding sites in brain areas that naturally express higher levels of beta-arrestin2. Cortex from beta-arrestin2-/- mice contained less CB1 in the P1 fraction and more CB1 in the P2 fraction compared to beta-arrestin2+/+. Of the agonists assayed for activity, only Δ(9)-tetrahydrocannabinol (THC) exhibited a difference between genotypes, in that it was less efficacious in beta-arrestin2-/- than +/+ mouse membranes.

CONCLUSION:

Beta-arrestin2 regulates cannabinoid CB1 receptors in brain.

PMID:
24094141
[PubMed - indexed for MEDLINE]
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