Adenosine-to-inosine RNA Editing Affects Trafficking of the Gamma-aminobutyric Acid Type A (GABA(A)) Receptor

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 Oct 30

PMID 21030585

Citations 48

Authors

Chammiran Daniel

Helene Wahlstedt

Johan Ohlson

Petra Bjork

Marie Ohman

Affiliations

Soon will be listed here.

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.

Citing Articles

Region and layer-specific expression of GABA receptor isoforms and KCC2 in developing cortex.

Zavalin K, Hassan A, Zhang Y, Khera Z, Lagrange A Front Cell Neurosci. 2024; 18:1390742.

PMID: 38894703 PMC: 11184147. DOI: 10.3389/fncel.2024.1390742.

RNA editing of ion channels and receptors in physiology and neurological disorders.

Zhai J, Koh J, Soong T Oxf Open Neurosci. 2024; 1:kvac010.

PMID: 38596706 PMC: 11003377. DOI: 10.1093/oons/kvac010.

Recommendations for detection, validation, and evaluation of RNA editing events in cardiovascular and neurological/neurodegenerative diseases.

Karagianni K, Bibi A, Made A, Acharya S, Parkkonen M, Barbalata T Mol Ther Nucleic Acids. 2024; 35(1):102085.

PMID: 38192612 PMC: 10772297. DOI: 10.1016/j.omtn.2023.102085.

Do RNA modifications contribute to modulation of immune responses in allergic diseases?.

Kudrin P, Rebane A Front Allergy. 2023; 4:1277244.

PMID: 38026133 PMC: 10679440. DOI: 10.3389/falgy.2023.1277244.

Programmable RNA editing with endogenous ADAR enzymes - a feasible option for the treatment of inherited retinal disease?.

Bellingrath J, McClements M, Fischer M, MacLaren R Front Mol Neurosci. 2023; 16:1092913.

PMID: 37293541 PMC: 10244592. DOI: 10.3389/fnmol.2023.1092913.

References

Lomeli H, Mosbacher J, Melcher T, Hoger T, Geiger J, Kuner T . Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science. 1994; 266(5191):1709-13. DOI: 10.1126/science.7992055. View

Greger I, Khatri L, Ziff E . RNA editing at arg607 controls AMPA receptor exit from the endoplasmic reticulum. Neuron. 2002; 34(5):759-72. DOI: 10.1016/s0896-6273(02)00693-1. View

Baumann S, Baur R, Sigel E . Forced subunit assembly in alpha1beta2gamma2 GABAA receptors. Insight into the absolute arrangement. J Biol Chem. 2002; 277(48):46020-5. DOI: 10.1074/jbc.M207663200. View

Gingrich K, Roberts W, Kass R . Dependence of the GABAA receptor gating kinetics on the alpha-subunit isoform: implications for structure-function relations and synaptic transmission. J Physiol. 1995; 489 ( Pt 2):529-43. PMC: 1156777. DOI: 10.1113/jphysiol.1995.sp021070. View

Korpi E, Luddens H . Regional gamma-aminobutyric acid sensitivity of t-butylbicyclophosphoro[35S]thionate binding depends on gamma-aminobutyric acidA receptor alpha subunit. Mol Pharmacol. 1993; 44(1):87-92. View

Enstero M, Akerborg O, Lundin D, Wang B, Furey T, Ohman M . A computational screen for site selective A-to-I editing detects novel sites in neuron specific Hu proteins. BMC Bioinformatics. 2010; 11:6. PMC: 2831006. DOI: 10.1186/1471-2105-11-6. View

Gorrie G, Vallis Y, Stephenson A, Whitfield J, Browning B, Smart T . Assembly of GABAA receptors composed of alpha1 and beta2 subunits in both cultured neurons and fibroblasts. J Neurosci. 1997; 17(17):6587-96. PMC: 6573131. View

Margulies M, Egholm M, Altman W, Attiya S, Bader J, Bemben L . Genome sequencing in microfabricated high-density picolitre reactors. Nature. 2005; 437(7057):376-80. PMC: 1464427. DOI: 10.1038/nature03959. View

Fritschy J, Paysan J, Enna A, Mohler H . Switch in the expression of rat GABAA-receptor subtypes during postnatal development: an immunohistochemical study. J Neurosci. 1994; 14(9):5302-24. PMC: 6577100. View

10.

Ramadan E, Fu Z, Losi G, Homanics G, Neale J, Vicini S . GABA(A) receptor beta3 subunit deletion decreases alpha2/3 subunits and IPSC duration. J Neurophysiol. 2003; 89(1):128-34. DOI: 10.1152/jn.00700.2002. View

11.

Kittler J, Delmas P, Jovanovic J, Brown D, Smart T, Moss S . Constitutive endocytosis of GABAA receptors by an association with the adaptin AP2 complex modulates inhibitory synaptic currents in hippocampal neurons. J Neurosci. 2000; 20(21):7972-7. PMC: 6772725. View

12.

Wisden W, Laurie D, Monyer H, Seeburg P . The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J Neurosci. 1992; 12(3):1040-62. PMC: 6576059. View

13.

Aruscavage P, Bass B . A phylogenetic analysis reveals an unusual sequence conservation within introns involved in RNA editing. RNA. 2000; 6(2):257-69. PMC: 1369911. DOI: 10.1017/s1355838200991921. View

14.

Henneberger C, Juttner R, Schmidt S, Walter J, Meier J, Rothe T . GluR- and TrkB-mediated maturation of GABA receptor function during the period of eye opening. Eur J Neurosci. 2005; 21(2):431-40. DOI: 10.1111/j.1460-9568.2005.03869.x. View

15.

Feldmeyer D, Kask K, Brusa R, Kornau H, Kolhekar R, Rozov A . Neurological dysfunctions in mice expressing different levels of the Q/R site-unedited AMPAR subunit GluR-B. Nat Neurosci. 1999; 2(1):57-64. DOI: 10.1038/4561. View

16.

Nimmich M, Heidelberg L, Fisher J . RNA editing of the GABA(A) receptor alpha3 subunit alters the functional properties of recombinant receptors. Neurosci Res. 2009; 63(4):288-93. PMC: 2775542. DOI: 10.1016/j.neures.2009.01.003. View

17.

Wahlstedt H, Daniel C, Enstero M, Ohman M . Large-scale mRNA sequencing determines global regulation of RNA editing during brain development. Genome Res. 2009; 19(6):978-86. PMC: 2694479. DOI: 10.1101/gr.089409.108. View

18.

Benke D, Mertens S, Trzeciak A, Gillessen D, Mohler H . GABAA receptors display association of gamma 2-subunit with alpha 1- and beta 2/3-subunits. J Biol Chem. 1991; 266(7):4478-83. View

19.

Kittler J, Thomas P, Tretter V, Bogdanov Y, Haucke V, Smart T . Huntingtin-associated protein 1 regulates inhibitory synaptic transmission by modulating gamma-aminobutyric acid type A receptor membrane trafficking. Proc Natl Acad Sci U S A. 2004; 101(34):12736-41. PMC: 515122. DOI: 10.1073/pnas.0401860101. View

20.

McKernan R, Whiting P . Which GABAA-receptor subtypes really occur in the brain?. Trends Neurosci. 1996; 19(4):139-43. DOI: 10.1016/s0166-2236(96)80023-3. View