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RNA editing produces glycine receptor α3P185L, resulting in high agonist potency

Nature Neuroscience volume 8, pages 736–744 (2005)Cite this article

Abstract

The function of supramedullary glycine receptors (GlyRs) is still unclear. Using Wistar rat collicular slices, we demonstrate GlyR-mediated inhibition of spike discharge elicited by low glycine (10 μM). Searching for the molecular basis of this phenomenon, we identified a new GlyR isoform. GlyRα3P185L, a result of cytidine 554 deamination, confers high glycine sensitivity (EC50 ∼5 μM) to neurons and thereby promotes the generation of sustained chloride conductances associated with tonic inhibition. The level of GlyRα3-C554U RNA editing is sensitive to experimentally induced brain lesion, inhibition of cytidine deamination by zebularine and inhibition of mRNA transcription by actinomycin D, but not to blockade of protein synthesis by cycloheximide. Conditional regulation of GlyRα3P185L is thus likely to be part of a post-transcriptional adaptive mechanism in neurons with enhanced excitability.

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Figure 1: Inhibition of spontaneous spike discharge by low glycine in P15 dorsal midbrain slices, and GlyR structure.
Figure 2: Detection of GlyRα3-C554U transcripts in situ.
Figure 3: Concentration-response relations for cultured hippocampal neurons expressing GlyRα3 and α3P185L.
Figure 4: Characteristics of current desensitization and tonic glycine-induced currents in cultured hippocampal neurons expressing GlyRα3 or α3P185L.
Figure 5: Localization and functional assessment of GlyRα3 in perinatal (E21–P1) dorsal midbrain slices.

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Acknowledgements

We thank U. Neumann for excellent technical assistance and S. Kirischuk for comments on earlier versions of the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft (grant SFB 515 B2 to R.G.), by Charité University Medicine funding, and by the Medical Research Council (R.J.H.).

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Author notes

  1. Igor Melnick

    Present address: Bogomoletz Institute of Physiology, Bogomoletz Str. 4, Kiev, 01024, Ukraine

Authors and Affiliations

  1. Department of Developmental Physiology, Johannes-Mueller Center of Physiology, Charité University Medicine, Berlin, 10117, Germany

    Jochen C Meier, Christian Henneberger, Igor Melnick & Rosemarie Grantyn

  2. School of Biomedical Sciences, University of Leeds, Leeds, LS2 9JT, UK

    Claudia Racca

  3. Department of Pharmacology, The School of Pharmacy, London, WC1N 1AX, UK

    Robert J Harvey

  4. Department of Cellular Neurophysiology, Johannes-Mueller Center of Physiology, Charité University Medicine, Berlin, 10117, Germany

    Uwe Heinemann & Volker Schmieden

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Supplementary Figure 1

Distribution of GlyRα3 in the adult brain. (PDF 570 kb)

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Meier, J., Henneberger, C., Melnick, I. et al. RNA editing produces glycine receptor α3P185L, resulting in high agonist potency. Nat Neurosci 8, 736–744 (2005). https://doi.org/10.1038/nn1467

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