RNA editing of the GABAA receptor α3 subunit alters the functional properties of recombinant receptors

RNA editing provides a post-transcriptional mechanism to increase structural heterogeneity of gene products. Recently, the alpha 3 subunit of the GABA(A) receptors has been shown to undergo RNA editing. As a result, a highly conserved isoleucine residue in the third transmembrane domain is replaced with a methionine. To determine the effect of this structural change on receptor function, we compared the GABA sensitivity, pharmacological properties and macroscopic kinetics of recombinant receptors containing either the edited or unedited forms of the alpha 3 subunit along with beta 3 and gamma 2L. Editing substantially altered the GABA sensitivity and deactivation rate of the receptors, with the unedited form showing a lower GABA EC50 and slower decay. Comparable effects were observed with a mutation at the homologous location in the alpha 1 subunit, suggesting a common role for this site in regulation of channel gating. Except for the response to GABA, the pharmacological properties of the receptor were unaffected by editing, with similar enhancement by a variety of modulators. Since RNA editing of the alpha 3 subunit increases through development, our findings suggest that GABAergic neurotransmission may be more effective early in development, with greater GABA sensitivity and slower decay rates conferred by the unedited alpha 3 subunit. (C) 2009 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.