O. Taleb et H. Betz, EXPRESSION OF THE HUMAN GLYCINE RECEPTOR ALPHA-1-SUBUNIT IN XENOPUS-OOCYTES - APPARENT AFFINITIES OF AGONISTS INCREASE AT HIGH RECEPTOR DENSITY, EMBO journal, 13(6), 1994, pp. 1318-1324
The inhibitory glycine receptor (GlyR) is a ligand-gated chloride chan
nel, which mediates post-synaptic inhibition in spinal cord and other
brain regions. Heterologous expression of the ligand binding ce subuni
ts of the GlyR generates functional agonist-gated chloride channels th
at mimic most of the pharmacological properties of the receptor in viv
o. Here, nuclear injection into Xenopus oocytes of a human alpha1 subu
nit cDNA, engineered for efficient expression, was used to create GlyR
channels over a wide density range, resulting in whole-cell glycine c
urrents of 10 nA to 25 muA. Notably, the pharmacology of these channel
s changed at high expression levels, with the appearance of a novel re
ceptor subpopulation of 5-to 6-fold higher apparent agonist affinity a
t current values > 4 muA. The low-affinity receptors were readily bloc
ked by nM concentrations of the competitive antagonist strychnine, whe
reas the high-affinity receptors were more resistant to antagonism by
this alkaloid. Picrotoxinin, a chloride channel blocker, inhibited bot
h GlyR populations with equal potency. Our data suggest that receptor
interactions, occurring at high receptor density, modify the agonist r
esponse of the GlyR. This phenomenon may contribute to neurotransmitte
r efficacy at fast synapses.