Electrophysiological characterisation of the actions of kynurenic acid at ligand-gated ion channels

To better understand the effects of the tryptophan metabolite kynurenic acid (kynA) in the brain, we characterised its actions at five ligand-gated ion channels: NMDA, AMPA, GABA(A), glycine and alpha 7 nicotinic acetylcholine receptors. Using whole-cell patch-clamp recordings, we found that kynA was a more potent antagonist at human NR1a/NR2A compared with NR1a/NR2B receptors (IC(50): 158 mu M and 681 mu M, respectively; in 30 mu M glycine). KynA inhibited AMPA-evoked currents to a similar degree in cultured hippocampal neurons and a human GluR2(flip/unedited) cell line (IC(50): 433 and 596 mu M, respectively) and at higher concentrations, kynA also inhibited the strychnine-sensitive glycine receptor (similar to 35% inhibition by 3 mM kynA). Interestingly, kynA inhibited the peak amplitude (IC(50): 2.9 mM for 10 mu M GABA) and slowed the decay kinetics of GABA-evoked currents in cultured neurons. In contrast, we found that kynA (1-3 mM) had no effect on ACh-evoked, methyllycaconitine (MLA)-sensitive currents in a human alpha 7 nicotinic receptor (nAChR) cell line, rat hippocampal neurons in primary culture or CA1 stratum radiatum interneurons in rat brain slices. However, DMSO (>1%) did inhibit alpha 7 nAChR-mediated currents. In conclusion, kynA is an antagonist at NMDA, AMPA and glycine receptors and a modulator of GABAA receptors, but we find no evidence for any effect of kynA at the alpha 7 nAChR. (C) 2009 Elsevier Ltd. All rights reserved.