Mutation of an arginine residue in the human glycine receptor transforms beta-alanine and taurine from agonists into competitive antagonists.
Agonist binding to the inhibitory glycine receptor (GlyR) initiates the opening of a chloride-selective channel that modulates the neuronal membrane potential. Point mutations of the GlyR, substituting Arg-271 with either Leu or Gln, have been shown to underlie the inherited neurological disorder startle disease (hyperekplexia). We show that these substitutions result in the redistribution of GlyR single-channel conductances to lower conductance levels. Additionally, the binding of the glycinergic agonists beta-alanine and taurine to mutated GlyRs does not initiate a chloride current, but instead competitively antagonizes currents activated by glycine. These findings are consistent with mutations of Arg-271 resulting in the uncoupling of the agonist binding process from the channel activation mechanism of the receptor.
Rajendra
S
S
School of Physiology and Pharmacology, University of New South Wales, Sydney, Australia.
Lynch
J W
JW
Pierce
K D
KD
French
C R
CR
Barry
P H
PH
Schofield
P R
PR
D001120:Arginine / Q000235:genetics*; D001667:Binding, Competitive; D002461:Cell Line, Transformed; D018118:Chloride Channels / Q000502:physiology; D004553:Electric Conductivity; D006801:Humans; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D018009:Receptors, Glycine / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D013329:Structure-Activity Relationship; D013331:Strychnine / Q000378:metabolism; D013654:Taurine / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection; D015091:beta-Alanine / Q000378:metabolism / Q000494:pharmacology*
D018118:Chloride Channels; D018009:Receptors, Glycine; D015091:beta-Alanine; D013654:Taurine; D001120:Arginine; D013331:Strychnine