Altered RNA editing of serotonin 5-HT2C receptor induced by interferon: implications for depression associated with cytokine therapy

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-HT2CR) 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-HT2CR. Interferon-α (IFN-α) often causes severe depression in patients treated for chronic viral hepatitis and certain malignancies. In this study, we examined the effects of IFN-α on RNA editing in human glioblastoma cell lines, which express 5-HT2CR mRNAs. ADAR1 expression and the pattern of the 5-HT2CR mRNA editing rapidly changed in response to IFN-α, leading to the dominant expression of the 5-HT2CR-VSI isoform predicted to have reduced G-protein coupling functions. Our results support the hypothesis that 5-HT2CR mRNA editing has causative relevance in the pathophysiology of depression associated with cytokine therapy.