title: Cannabinoid 2 receptor- and beta Arrestin 2-dependent upregulation of serotonin 2A receptors.
abstract: Recent evidence suggests that cannabinoid receptor agonists may regulate serotonin 2A (5-HT(2A)) receptor neurotransmission in the brain, although no molecular mechanism has been identified. Here, we present experimental evidence that sustained treatment with a non-selective cannabinoid agonist (CP55,940) or selective CB2 receptor agonists (JWH133 or GP1a) upregulate 5-HT(2A) receptors in a neuronal cell line. Furthermore, this cannabinoid receptor agonist-induced upregulation of 5-HT(2A) receptors was prevented in cells stably transfected with either CB2 or β-Arrestin 2 shRNA lentiviral particles. Additionally, inhibition of clathrin-mediated endocytosis also prevented the cannabinoid receptor-induced upregulation of 5-HT(2A) receptors. Our results indicate that cannabinoid agonists might upregulate 5-HT(2A) receptors by a mechanism that requires CB2 receptors and β-Arrestin 2 in cells that express both CB2 and 5-HT(2A) receptors. 5-HT(2A) receptors have been associated with several physiological functions and neuropsychiatric disorders such as stress response, anxiety and depression, and schizophrenia. Therefore, these results might provide a molecular mechanism by which activation of cannabinoid receptors might be relevant to some cognitive and mood disorders in humans.
authors: Department of Pharmacology and Toxicology, University of Kansas, 1251 Wescoe Hall Drive, 3048B Malott Hall, Lawrence, KS 66045, United States.
authors: J M
authors: JM
authors: Franklin
authors: T
authors: T
authors: Vasiljevik
authors: T E
authors: TE
authors: Prisinzano
authors: G A
authors: GA
authors: Carrasco
mesh_terms: D000818:Animals; D019390:Arrestins / Q000819:agonists* / Q000235:genetics / Q000502:physiology*; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology*; D002186:Cannabinoids / Q000494:pharmacology; D002478:Cells, Cultured; D002966:Clathrin / Q000494:pharmacology; D003511:Cyclohexanols / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D007192:Indenes / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000235:genetics / Q000502:physiology*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; C000605257:Arrb2 protein, rat; D019390:Arrestins; D063386:Cannabinoid Receptor Agonists; D002186:Cannabinoids; D002966:Clathrin; D003511:Cyclohexanols; D007192:Indenes; C553580:N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-1,4-dihydro-6-methylindeno(1,2-c)pyrazole-3-carboxamide; D011720:Pyrazoles; D034741:RNA, Small Interfering; 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; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC