Mutation of an arginine residue in the human glycine receptor transforms β-alanine and taurine from agonists into competitive antagonists

Abstract

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 GIyR, substituting Arg271 with either Leu or Gin, have been shown to underlie the inherited neurological disorder startle disease (hyperekplexia). We show that these substitutions result in the redistribution of GIyR single-channel conductances to lower conductance levels. Additionally, the binding of the glycinergic agonists β-alanine and taurine to mutated GIyRs 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.