RNA editing of the human serotonin 5-HT_2C receptor: Alterations in suicide and implications for serotonergic pharmacotherapy

RNA encoding the human serotonin 5-HT_2C receptor (5-HT_2CR) undergoes adenosine-to-inosine RNA editing events at five positions, resulting in an alteration of amino acids in the second intracellular loop. Several edited 5-HT_2CRs possess a reduced G-protein coupling efficiency compared to the completely non-edited isoform. The current studies show that the efficacy of the hallucinogenic drug lysergic acid diethylamide and of antipsychotic drugs is regulated by RNA editing, suggesting that alterations in editing efficiencies or patterns might result in the generation of a 5-HT_2CR population differentially responsive to serotonergic drugs. An examination of the efficiencies of RNA editing of the 5-HT_2CR in prefrontal cortex of control individuals vs. subjects diagnosed with schizophrenia or major depressive disorder revealed no significant differences in RNA editing among the three populations. However, subjects who had committed suicide (regardless of diagnosis) exhibited a statistically significant elevation of editing at the A-site, which is predicted to change the amino acid sequence in the second intracellular loop of the 5-HT_2CR. These findings suggest that alterations in RNA editing may contribute to or complicate therapy in certain psychiatric disorders.