title: Contributions of different kainate receptor subunits to the properties of recombinant homomeric and heteromeric receptors.
abstract: The tetrameric kainate receptors can be assembled from a combination of five different subunit subtypes. While GluK1-3 subunits can form homomeric receptors, GluK4 and GluK5 require a heteromeric partner to assemble, traffic to the membrane surface, and produce a functional channel. Previous studies have shown that incorporation of a GluK4 or GluK5 subunit changes both receptor pharmacology and channel kinetics. We directly compared the functional characteristics of recombinant receptors containing either GluK4 or GluK5 in combination with the GluK1 or GluK2 subunit. In addition, we took advantage of mutations within the agonist binding sites of GluK1, GluK2, or GluK5 to isolate the response of the wild-type partner within the heteromeric receptor. Our results suggest that GluK1 and GluK2 differ primarily in their pharmacological properties, but that GluK4 and GluK5 have distinct functional characteristics. In particular, while binding of agonist to only the GluK5 subunit appears to activate the channel to a non-desensitizing state, binding to GluK4 does produce some desensitization. This suggests that GluK4 and GluK5 differ fundamentally in their contribution to receptor desensitization. In addition, mutation of the agonist binding site of GluK5 results in a heteromeric receptor with a glutamate sensitivity similar to homomeric GluK1 or GluK2 receptors, but which requires higher agonist concentrations to produce desensitization. This suggests that onset of desensitization in heteromeric receptors is determined more by the number of subunits bound to agonist than by the identity of those subunits. The distinct, concentration-dependent properties observed with heteromeric receptors in response to glutamate or kainate are consistent with a model in which either subunit can activate the channel, but in which occupancy of both subunits within a dimer is needed to allow desensitization of GluK2/K5 receptors.
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Fisher
authors.affiliation: Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA. Electronic address: jfisher@uscmed.sc.edu.
authors.forename: J L
authors.initials: JL
authors.lastname: Fisher
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D018698:Glutamic Acid / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D009154:Mutation; D021122:Protein Subunits / Q000235:genetics / Q000502:physiology; D051381:Rats; D018092:Kainic Acid Receptors / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins; D000097806:GluK2 Kainate Receptor
chemical_list: D018698:Glutamic Acid; D021122:Protein Subunits; D018092:Kainic Acid Receptors; D011994:Recombinant Proteins; D000097806:GluK2 Kainate Receptor
keywords: glutamate; kainate receptors; mutagenesis; patch-clamp