The diversity of synaptic signaling is partly generated by the presence of multiple receptor isoforms that respond to a neurotransmitter by activating separate downstream signals. In the mammalian central nervous system, the repertoire of receptors is expanded beyond the genomically encoded set by a process known as A-to-I RNA editing. It has been discovered that adenosines are converted to inosines within duplexes formed by precurser-mRNAs that code for several ionotropic glutamate receptor subunits and the 2C-subtype of the serotonin receptor (5-HT2cR), and the resulting altered mRNAs code for functionally distinct receptors. Two double-stranded RNA binding adenosine deaminases called ADAR1 and ADAR2 are responsible for precise A-to-I editing of those neuronal transcripts. Recent studies suggest that the appropriate regulation of the expression of ADAR2 is critical for maintaining editing site selectivity, and misregulation of ADAR2 expression in mice leads to extreme obesity (Emeson, unpublished results). A newly discovered A-to-I editing event in the pre-mRNA encoding ADAR2 itself suggests that a quite unique form of regulation of ADAR2 activity occurs, where ADAR2 may negatively regulate its own expression by editing its own transcript. The ultimate aim of this proposal is to test the significance of ADAR2 autoediting. This will be accomplished by studying ADAR2 mRNA and protein expression in mice genetically engineered to lack ADAR2 autoediting, and the resulting changes of editing patterns in known substrates of ADAR2 will be examined.
