title: Electrophysiological characterisation of the actions of kynurenic acid at ligand-gated ion channels.
abstract: 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 alpha7 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 muM and 681 muM, respectively; in 30 muM 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 muM, respectively) and at higher concentrations, kynA also inhibited the strychnine-sensitive glycine receptor ( approximately 35% inhibition by 3 mM kynA). Interestingly, kynA inhibited the peak amplitude (IC(50): 2.9 mM for 10 muM 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 alpha7 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 alpha7 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 alpha7 nAChR.
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex CM19 5AW, United Kingdom. selina.mok@gsk.com
authors.forename: M H Selina
authors.initials: MH
authors.lastname: Mok
authors.forename: Anne-Cécile
authors.initials: AC
authors.lastname: Fricker
authors.forename: Annette
authors.initials: A
authors.lastname: Weil
authors.forename: James N C
authors.initials: JN
authors.lastname: Kew
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism*; D007700:Kinetics; D007736:Kynurenic Acid / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; D018691:Excitatory Amino Acid Antagonists; D007473:Ion Channels; D018091:Receptors, AMPA; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D007736:Kynurenic Acid