title: G-protein receptor kinase 5 regulates the cannabinoid receptor 2-induced up-regulation of serotonin 2A receptors.
abstract: We have recently reported that cannabinoid agonists can up-regulate and enhance the activity of serotonin 2A (5-HT2A) receptors in the prefrontal cortex (PFCx). Increased expression and activity of cortical 5-HT2A receptors has been associated with neuropsychiatric disorders, such as anxiety and schizophrenia. Here we report that repeated CP55940 exposure selectively up-regulates GRK5 proteins in rat PFCx and in a neuronal cell culture model. We sought to examine the mechanism underlying the regulation of GRK5 and to identify the role of GRK5 in the cannabinoid agonist-induced up-regulation and enhanced activity of 5-HT2A receptors. Interestingly, we found that cannabinoid agonist-induced up-regulation of GRK5 involves CB2 receptors, β-arrestin 2, and ERK1/2 signaling because treatment with CB2 shRNA lentiviral particles, β-arrestin 2 shRNA lentiviral particles, or ERK1/2 inhibitor prevented the cannabinoid agonist-induced up-regulation of GRK5. Most importantly, we found that GRK5 shRNA lentiviral particle treatment prevented the cannabinoid agonist-induced up-regulation and enhanced 5-HT2A receptor-mediated calcium release. Repeated cannabinoid exposure was also associated with enhanced phosphorylation of CB2 receptors and increased interaction between β-arrestin 2 and ERK1/2. These latter phenomena were also significantly inhibited by GRK5 shRNA lentiviral treatment. Our results suggest that sustained activation of CB2 receptors, which up-regulates 5-HT2A receptor signaling, enhances GRK5 expression; the phosphorylation of CB2 receptors; and the β-arrestin 2/ERK interactions. These data could provide a rationale for some of the adverse effects associated with repeated cannabinoid agonist exposure.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas 66045, USA.
authors.forename: Jade M
authors.initials: JM
authors.lastname: Franklin
authors.forename: Gonzalo A
authors.initials: GA
authors.lastname: Carrasco
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D018929:Cell Culture Techniques; D003511:Cyclohexanols / Q000494:pharmacology*; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016086:Lentivirus; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000096:biosynthesis* / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D000700:Analgesics; C000605258:Arrb2 protein, mouse; C000605257:Arrb2 protein, rat; D019390:Arrestins; C469526:Cnr2 protein, rat; D003511:Cyclohexanols; D009419:Nerve Tissue Proteins; D043885:Receptor, Cannabinoid, CB2; D044402:Receptor, Serotonin, 5-HT2A; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D054774:G-Protein-Coupled Receptor Kinase 5; C517897:Grk5 protein, rat; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium
keywords: 5-HT2A Receptor; Arrestin; CB2 Receptor; Cannabinoid Receptors; Cannabinoids; GRK Proteins; Molecular Pharmacology; Receptor Regulation; β-Arrestin