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

• Published in: Neuropharmacology 2009-09, Vol.57 (3), p.242-249
• Main Authors: Mok, M.H. Selina, Fricker, Anne-Cécile, Weil, Annette, Kew, James N.C.
• Format: Article
• Language: English
• Subjects: alpha7 Nicotinic Acetylcholine Receptor; Animals; Brain - drug effects; Brain - physiology; Cell Line; Cells, Cultured; DMSO; Excitatory Amino Acid Antagonists - pharmacology; GABA-A receptor; Glycine receptor; Hippocampus - drug effects; Hippocampus - physiology; Humans; In Vitro Techniques; Ion Channel Gating; Ion Channels - metabolism; Kinetics; Kynurenic acid; Kynurenic Acid - pharmacology; Neurons - drug effects; Neurons - physiology; NMDA receptor; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Receptors, AMPA - antagonists & inhibitors; Receptors, AMPA - metabolism; Receptors, GABA-A - metabolism; Receptors, Glycine - antagonists & inhibitors; Receptors, Glycine - metabolism; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; Receptors, Nicotinic - metabolism; α7 Nicotinic receptor
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2009.06.003

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 α7 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 μM and 681 μM, respectively; in 30 μM 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 μM, respectively) and at higher concentrations, kynA also inhibited the strychnine-sensitive glycine receptor (∼35% inhibition by 3 mM kynA). Interestingly, kynA inhibited the peak amplitude (IC 50: 2.9 mM for 10 μM 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 α7 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 α7 nAChR-mediated currents. In conclusion, kynA is an antagonist at NMDA, AMPA and glycine receptors and a modulator of GABA A receptors, but we find no evidence for any effect of kynA at the α7 nAChR.