Kynurenic acid has a dual action on AMPA receptor responses.
Glutamate is the predominant excitatory neurotransmitter in the central nervous system. The receptors that bind glutamate, including N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subtypes, are strongly implicated in higher cognitive processes, especially learning and memory. Loss of glutamate receptor function impairs the ability to acquire and retain information in some patients subsequent to stroke or brain injury, and positive allosteric modulators of glutamate receptors can restore learning and memory in some of these patients. Here we demonstrate that kynurenic acid (KYNA), an endogenous tryptophan metabolite, acts upon heterologous AMPA receptors via two distinct mechanisms. Low (nanomolar to micromolar) concentrations of KYNA facilitate AMPA receptor responses, whereas high (millimolar) concentrations of KYNA competitively antagonize glutamate receptors. Low concentrations of KYNA appear to increase current responses through allosteric modulation of desensitization of AMPA receptors. These findings suggest the possibility that low concentrations of endogenous KYNA acting at AMPA receptors may be a positive modulator of excitatory synaptic transmission.
Prescott
Christina
C
Department of Neurology and Pediatrics, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Weeks
Autumn M
AM
Staley
Kevin J
KJ
Partin
Kathryn M
KM
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D007736:Kynurenic Acid / Q000378:metabolism* / Q000494:pharmacology; D007930:Leucine / Q000235:genetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D016296:Mutagenesis / Q000502:physiology; D009865:Oocytes; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000502:physiology*; D014443:Tyrosine / Q000235:genetics; D014982:Xenopus laevis
D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D018698:Glutamic Acid; D014443:Tyrosine; D007930:Leucine; D007736:Kynurenic Acid