title: Altered RNA editing of serotonin 5-HT2C receptor induced by interferon: implications for depression associated with cytokine therapy.
abstract: Members of the ADAR (adenosine deaminases acting on RNA) gene family are involved in one type of RNA editing that converts adenosine residues to inosine. The A-to-I editing of serotonin receptor subtype 2C (5-HT(2C)R) mRNA leads to replacement of three amino acid residues located within the intracellular loop II domain, resulting in dramatic alterations in G-protein coupling functions of the receptor. It has been speculated that RNA editing may play a role in several pharmacological and behavioral processes where the serotonergic plasticity is mediated through 5-HT(2C)R. Interferon-alpha (IFN-alpha) often causes severe depression in patients treated for chronic viral hepatitis and certain malignancies. In this study, we examined the effects of IFN-alpha on RNA editing in human glioblastoma cell lines, which express 5-HT(2C)R mRNAs. ADAR1 expression and the pattern of the 5-HT(2C)R mRNA editing rapidly changed in response to IFN-alpha, leading to the dominant expression of the 5-HT(2C)R-VSI isoform predicted to have reduced G-protein coupling functions. Our results support the hypothesis that 5-HT(2C)R mRNA editing has causative relevance in the pathophysiology of depression associated with cytokine therapy.
authors.affiliation: The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Weidong
authors.initials: W
authors.lastname: Yang
authors.forename: Qingde
authors.initials: Q
authors.lastname: Wang
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kanes
authors.forename: John M
authors.initials: JM
authors.lastname: Murray
authors.forename: Kazuko
authors.initials: K
authors.lastname: Nishikura
mesh_terms: D000243:Adenosine Deaminase / Q000378:metabolism; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D045744:Cell Line, Tumor; D016207:Cytokines / Q000627:therapeutic use; D003863:Depression / Q000139:chemically induced; D005786:Gene Expression Regulation / Q000187:drug effects; D005909:Glioblastoma; D006801:Humans; D007372:Interferons / Q000009:adverse effects / Q000494:pharmacology*; D008957:Models, Genetic; D017393:RNA Editing / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D044405:Receptor, Serotonin, 5-HT2C; D007372:Interferons; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase