title: Cannabinoid agonists increase the interaction between β-Arrestin 2 and ERK1/2 and upregulate β-Arrestin 2 and 5-HT(2A) receptors.
abstract: We have recently reported that selective cannabinoid 2 (CB(2)) receptor agonists upregulate 5-HT(2A) receptors by enhancing ERK1/2 signaling in prefrontal cortex (PFCx). Increased activity of cortical 5-HT(2A) receptors has been associated with several neuropsychiatric disorders such as anxiety and schizophrenia. Here we examine the mechanisms involved in this enhanced ERK1/2 activation in rat PFCx and in a neuronal cell model. Sprague-Dawley rats treated with a non-selective cannabinoid agonist (CP55940, 50μg/kg, 7 days, i.p.) showed enhanced co-immunoprecipitation of β-Arrestin 2 and ERK1/2, enhanced pERK protein levels, and enhanced expression of β-Arrestin 2 mRNA and protein levels in PFCx. In a neuronal cell line, we found that selective CB(2) receptor agonists upregulate β-Arrestin 2, an effect that was prevented by selective CB(2) receptor antagonist JTE-907 and CB(2) shRNA lentiviral particles. Additionally, inhibition of clathrin-mediated endocytosis, ERK1/2, and the AP-1 transcription factor also prevented the cannabinoid receptor-induced upregulation of β-Arrestin 2. Our results suggest that sustained activation of CB(2) receptors would enhance β-Arrestin 2 expression possibly contributing to its increased interaction with ERK1/2, thereby driving the upregulation of 5-HT(2A) receptors. The CB(2) receptor-mediated upregulation of β-Arrestin 2 would be mediated, at least in part, by an ERK1/2-dependent activation of AP-1. These data could provide the rationale for some of the adverse effects associated with repeated cannabinoid exposure and shed light on some CB(2) receptor agonists that could represent an alternative therapeutic because of their minimal effect on serotonergic neurotransmission.
authors.affiliation: Department of Pharmacology and Toxicology, University of Kansas, 1251 Wescoe Hall Drive, 3048B Malott Hall, Lawrence, KS 66045, United States.
authors.forename: Jade M
authors.initials: JM
authors.lastname: Franklin
authors.forename: Tamara
authors.initials: T
authors.lastname: Vasiljevik
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
authors.forename: Gonzalo A
authors.initials: GA
authors.lastname: Carrasco
mesh_terms: D000818:Animals; D019390:Arrestins / Q000096:biosynthesis* / Q000235:genetics; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology; D003208:Concanavalin A / Q000494:pharmacology; D003511:Cyclohexanols / Q000494:pharmacology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D044402:Receptor, Serotonin, 5-HT2A / Q000096:biosynthesis*; D015854:Up-Regulation; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605257:Arrb2 protein, rat; D019390:Arrestins; D063386:Cannabinoid Receptor Agonists; D063387:Cannabinoid Receptor Antagonists; D003511:Cyclohexanols; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D044402:Receptor, Serotonin, 5-HT2A; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D003208:Concanavalin A; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3