title: The neurotoxin domoate causes long-lasting inhibition of the kainate receptor GluK5 subunit.
abstract: Ionotropic glutamate receptors (iGluRs) are responsible for fast excitatory neurotransmission in the mammalian brain, and are critical regulators of neuronal activity and synaptic plasticity. The three main types of iGluRs (AMPA, NMDA, and kainate receptors) are composed of distinct subunit populations. The tetrameric kainate receptors can be assembled from a combination of five different types of subunits (GluK1-GluK5). GluK1-3 subunits are able to produce functional homomeric receptors, while GluK4-5 are obligate heteromers, and must assemble with a GluK1-3 subunit. The neurotoxin domoate is widely used as an agonist at kainate-type receptors because it produces a less desensitizing response compared to glutamate. We have identified an additional, subunit-dependent action of domoate at recombinant kainate receptors. When applied to heteromeric GluK2/K5 receptors, domoate generates a small, long-lasting, tonic current. In addition, brief exposure to domoate inhibits the GluK5 subunit, preventing its activation by other agonists for several minutes. These characteristics are not associated with the GluK1, K2, or K4 subunits and can be prevented by a mutation in GluK5 that reduces agonist binding affinity. The results also show that the domoate-bound, GluK2/K5 heteromeric receptors can be fully activated by agonists acting through the GluK2 subunit, suggesting that the subunits within the tetramer can function independently to open the ion channel, and that the domoate-bound state is not a desensitized or blocked conformation. This study describes new properties associated with domoate action at kainate receptors, and further characterizes the distinct roles played by different subunits in heteromeric receptors.
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC 29208, USA. Electronic address: jfisher@uscmed.sc.edu.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Fisher
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009154:Mutation; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D018092:Kainic Acid Receptors / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D000097806:GluK2 Kainate Receptor
chemical_list: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D007608:Kainic Acid; D009498:Neurotoxins; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor; C012301:domoic acid
keywords: Domoic acid; Electrophysiology; Kainate receptors