A-to-I RNA editing modulates the pharmacology of neuronal ion channels and receptors

The regulation of neuronal excitability is complex, as ion channels and neurotransmitter receptors are underlying a large variety of modulating effects. Alterations in the expression patterns of receptors or channel subunits as well as differential splicing contribute to the regulation of neuronal excitability. RNA editing is another and more recently explored mechanism to increase protein diversity, as the genomic recoding leads to new gene products with novel functional and pharmacological properties. In humans A-to-I RNA editing targets several neuronal receptors and channels, including GluR2/5/6 subunits, the Kv1.1 channel, and the 5-HT_2C receptor. Our review summarizes that RNA editing of these proteins does not only change protein function, but also the pharmacology and presumably the drug therapy in human diseases.     

A-to-I editing of the 5HT2C receptor and behaviour.

Site-specific deamination of five adenosine residues in the pre-mRNA of the serotonin 2C receptor, 5HT2CR, alters the amino acid sequence of the encoded protein. Such RNA editing can produce 32 mRNA variants, encoding 24 protein isoforms that vary in biochemical and pharmacological properties. Because serotonin functions in the regulation of mood and behaviour, modulation of serotonin signalling by RNA editing may be relevant to such psychiatric disorders as anxiety and depression. Several recent human studies have reported changes in 5HT2CR editing in schizophrenia, major depression or suicide, but results are variable and not conclusive. Rodent studies have begun to examine effects of drug treatments and stress. Understanding the importance of 5HT2CR editing in mood and behaviour will be assisted by experiments designed to analyse multiple strains of mice, in different behavioural tests, with optimal evaluation of the time course of molecular changes.