%0 Journal Article %A Brady K Atwood %A Jim Wager-Miller %A Christopher Haskins %A Alex Straiker %A Ken Mackie %T Functional selectivity in CB2 cannabinoid receptor signaling and regulation: implications for the therapeutic potential of CB2 ligands %D 2011 %R 10.1124/mol.111.074013 %J Molecular Pharmacology %P mol.111.074013 %X Receptor internalization increases the flexibility and scope of GPCR signaling. CB1 and CB2 cannabinoid receptors undergo internalization following sustained exposure to agonists. However, it is not known if different agonists internalize CB2 to different extents. Since CB2 is a promising therapeutic target, understanding its trafficking in response to different agonists is necessary for a complete understanding of its biology. Here we profile a number of cannabinoid receptor ligands and provide evidence for marked functional selectivity of cannabinoid receptor internalization. Classical, aminoalkylindole, bicyclic, cannabilactone and iminothiazole cannabinoid, and endocannabinoid ligands varied greatly in their effects on CB1 and CB2 trafficking. Our most striking finding was that WIN55,212-2 (and other aminoalkylindoles) failed to promote CB2 receptor internalization, while CP55,940 robustly internalized CB2 receptors. Furthermore, WIN55,212-2 competitively antagonized CP55,940-induced CB2 internalization. Despite these differences in internalization, both compounds activated CB2 receptors as measured by ERK1/2 phosphorylation and recruitment of β-arrestin2 to the membrane. In contrast, while CP55,940 inhibited voltage-gated calcium channels via CB2 receptor activation, WIN55,212-2 was ineffective on its own and antagonized the effects of CP55,940. Based on the differences we found between these two ligands we also tested the effects of other cannabinoids on these signaling pathways and found additional evidence for functional selectivity of CB2 ligands. These novel data highlight that WIN55,212-2 and other cannabinoids show strong functional selectivity at CB2 receptors and suggest that different classes of CB2 ligands may produce diverse physiological effects, emphasizing that each class needs to be separately evaluated for therapeutic efficacy. %U https://molpharm.aspetjournals.org/content/molpharm/early/2011/11/07/mol.111.074013.full.pdf