EXPRESSION OF THE HUMAN GLYCINE RECEPTOR ALPHA-1-SUBUNIT IN XENOPUS-OOCYTES - APPARENT AFFINITIES OF AGONISTS INCREASE AT HIGH RECEPTOR DENSITY

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.