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 cannabinoidCB₁ 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 CB₁receptors 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 Δ⁹-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 – as supplied by publisher]