RNA editing produces glycine receptor alpha3(P185L), resulting in high agonist potency.
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 microM). Searching for the molecular basis of this phenomenon, we identified a new GlyR isoform. GlyR alpha3(P185L), a result of cytidine 554 deamination, confers high glycine sensitivity (EC50 approximately 5 microM) to neurons and thereby promotes the generation of sustained chloride conductances associated with tonic inhibition. The level of GlyR alpha3-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 GlyR alpha3(P185L) is thus likely to be part of a post-transcriptional adaptive mechanism in neurons with enhanced excitability.
Meier
Jochen C
JC
Department of Developmental Physiology, Johannes-Mueller Center of Physiology, Charité University Medicine, 10117 Berlin, Germany. jochen.meier@charite.de
Henneberger
Christian
C
Melnick
Igor
I
Racca
Claudia
C
Harvey
Robert J
RJ
Heinemann
Uwe
U
Schmieden
Volker
V
Grantyn
Rosemarie
R
D000200:Action Potentials / Q000187:drug effects / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D065101:Chloride Channel Agonists; D018118:Chloride Channels / Q000187:drug effects / Q000235:genetics; D003562:Cytidine / Q000378:metabolism; D003641:Deamination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005998:Glycine / Q000378:metabolism / Q000494:pharmacology; D008969:Molecular Sequence Data; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000302:isolation & purification; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D017393:RNA Editing / Q000235:genetics*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000819:agonists / Q000235:genetics* / Q000302:isolation & purification; D013477:Superior Colliculi / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*
D065101:Chloride Channel Agonists; D018118:Chloride Channels; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D018009:Receptors, Glycine; C113965:glycine receptor alpha3 subunit; D003562:Cytidine; D005998:Glycine