Abstract
Recoding by adenosine-to-inosine RNA editing plays an important role in diversifying proteins involved in neurotransmission. We have previously shown that the Gabra-3 transcript, coding for the α3 subunit of the GABA(A) receptor is edited in mouse, causing an isoleucine to methionine (I/M) change. Here we show that this editing event is evolutionarily conserved from human to chicken. Analyzing recombinant GABA(A) receptor subunits expressed in HEK293 cells, our results suggest that editing at the I/M site in α3 has functional consequences on receptor expression. We demonstrate that I/M editing reduces the cell surface and the total number of α3 subunits. The reduction in cell surface levels is independent of the subunit combination as it is observed for α3 in combination with either the β2 or the β3 subunit. Further, an amino acid substitution at the corresponding I/M site in the α1 subunit has a similar effect on cell surface presentation, indicating the importance of this site for receptor trafficking. We show that the I/M editing during brain development is inversely related to the α3 protein abundance. Our results suggest that editing controls trafficking of α3-containing receptors and may therefore facilitate the switch of subunit compositions during development as well as the subcellular distribution of α subunits in the adult brain.
Highlights
Coupled receptor and thereby creating diverse isoforms of proteins essential for balanced neuronal kinetics
We have previously found that the mouse Gabra-3 transcript, coding for the ␣3 subunit of the GABAA receptor undergoes site-selective Adenosine to inosine (A-to-I) editing causing an isoleucine to methionine (I/M) change in the third transmembrane region (TM3) (4)
The Nucleotide Sequence Is Evolutionarily Conserved in the Vicinity of the Edited Site—Here we demonstrate that the RNA editing event, giving rise to an isoleucine-to-methionine change in the ␣3 subunit of the GABAA receptor occurs in all species from chicken to human
Summary
Coupled receptor and thereby creating diverse isoforms of proteins essential for balanced neuronal kinetics (reviewed in Ref. 1). The chloride-permeable (GABAA) receptors are the main mediators of fast inhibitory neurotransmission in the mammalian central nervous system (reviewed in Ref. 5). These heteropentameric ligand-gated chloride ion channels can be formed from at least 16 different subunits: ␣1– 6, 1–3, ␥1–3, ␦, ⑀, , and (6, 7). Receptors containing the ␣3 subunit are characterized by slow activation, desensitization, and deactivation and by low GABA sensitivity (13–16). These unique kinetic properties have been shown to play an important role in the maturation of developing neurons (17). We hypothesize that A-to-I editing decreases the amount of ␣3 subunit containing GABAA receptors, possibly in favor of ␣1 containing receptors that is more abundant in the adult brain
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