RNA Editing

RNA editing has been detected in eukaryotes ranging from single-celled protozoa to mammals and plants and is now recognized as a type of RNA process (posttranscriptional modification of RNA) that differs from the established processes of RNA splicing, 5' end formation, and 3' endonucleolytic cleavage and polyadenylation (DeCerbo and Carmichael 2005; Kable et al. 1997). The conversion of adenosine to inosine was observed first in yeast tRNA (Grosjean et al. 1996) but has since been detected in viral RNA transcripts and mammalian cellular RNA (Bass 1997; Simpson and Emeson 1996). The inosine residues generated from adenosines can alter the coding information of the transcripts, as inosine is synonymous for guanosine during transcript translation. For example, upon A-to-I editing, the CAC codon for histamine is transformed to CIC, coding for arginine. RNA editing can have dramatic consequences for the expression of genetic information, and in a number of cases it has been shown to lead to the expression of proteins not only with altered amino acid sequences from those predicted from the DNA sequence but also with altered biological functions (Bass 2002; Burns et al. 1997).

The enzymes for RNA editing are referred to as adenosine deaminases that act on RNA (ADARs). ADARs target RNA that is double-stranded and convert adenosines to inosines by catalyzing a hydrolytic deamination at the adenine base (Bass 2002). Mammals have several ADARs, of which two (ADAR1 andADAR2) are expressed in most tissues of the body (Seeburg and Hartner 2003). RNA editing may also catalyze the conversion of one or a few adenosines in a transcript to inosines (Maas et al. 1997; Stuart and Panigrahi 2002). On the other hand, RNA editing can convert numerous adenosines to inosines in RNA. This type of editing is thought to be the result of aberrant production of dsRNA (DeCerbo and Carmichael 2005) and has been suggested to lead to RNA degradation (Scadden and Smith 2001), nuclear retention (Zhang and Carmichael 2001), or even gene silencing (Wang et al. 2005).

The 5-HT2C receptor is a G protein-coupled receptor that is well known to have variants generated by A-to-I editing (Burns et al. 1997). 5-HT2C receptor transcripts can be edited at up to five sites, potentially generating 24 different receptor versions, and hence a diverse receptor population. The RNA-edited 5-HT2C receptor affects ligand affinity and the efficacy of G protein coupling (Berg et al. 2001; Wang et al. 2000; Yang et al. 2004). The unedited form of the 5-HT2C receptor has the highest affinity to serotonin and exhibits constitutive activity independent of serotonin levels. When RNA is edited, the basal activity of the 5-HT2C receptor is suppressed, and agonist potency and efficacy are modified.

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