Initially identified as an RNA modification in the anticodon loop of tRNAs from animal, plant and eubacterial origin, the deamination of adenosine-to-inosine by RNA editing has become increasingly recognized as an important RNA processing event to generate diversity in both the transcriptome and proteome and is essential for modulating the activity of numerous proteins critical for nervous system function. Here, we focus on the editing of transcripts encoding the 2C-subtype of serotonin receptor (5HT(2C)) to generate multiple receptor isoforms that differ in G-protein coupling efficacy and constitutive activity. 5HT(2C) receptors have been implicated in the regulation of anxiety, components of the stress response, and are thought to play a role in compulsive behavioral disorders, depression and drug addiction. A number of studies have been conducted to assess whether 5HT(2C) editing is altered in individuals suffering from psychiatric disorders, yet the results from these studies have been inconsistent, and thus inconclusive. This review provides a discussion of the challenges involved with characterizing 5HT(2C) editing patterns in human postmortem tissue samples and how differences in quantitative methodology have contributed to the observed inconsistencies between multiple laboratories. Additionally, we discuss new high-throughput sequencing tools, which provide an opportunity to overcome previous methodological challenges, and permit reliable systematic analyses of RNA editing in control and pathologic disease states.
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