title: The delta subfamily of glutamate receptors: characterization of receptor chimeras and mutants.
abstract: The delta receptors, GluD1 and GluD2, are regarded as a subfamily of the ionotropic glutamate receptors solely because of sequence homology. While they play important roles in cerebellar function and high-frequency hearing and appear to serve structural functions at synapses, ligand-gated ion channel function has not been observed. However, we have previously shown that GluD2 can form functional ion channels when grafted with the ligand binding domain of a kainate receptor. In this study, we characterized this chimera as well as additional rat delta receptor chimeras and point mutants in more detail. We found that the kainate receptor ligand binding domain renders GluD1 functional as well, and GluD2 becomes a functional ion channel also when provided with an AMPA receptor ligand binding domain. Point mutations indicate that the GluD2 ion pore operates similarly but not identically to that of AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and kainate receptors. GluD2 mutated at a conserved arginine within the linker region connecting the ligand binding domain to the ion pore domain displays spontaneous currents that occur in the absence of agonists and are inhibited by agonist application - a behavior reminiscent of that of the previously characterized lurcher mutant. Using our chimeric approach, we provide evidence that this inhibition of spontaneous currents by agonists may be caused by desensitization. Our results show that delta receptors have functional gating machineries and ion permeation pathways similar but not identical to those of AMPA and kainate receptors, while the key differences seem to be located within the ligand binding domain.
authors.affiliation: Department of Biochemistry I - Receptor Biochemistry, Ruhr University Bochum, Bochum, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Orth
authors.forename: Daniel
authors.initials: D
authors.lastname: Tapken
authors.forename: Michael
authors.initials: M
authors.lastname: Hollmann
mesh_terms: D000200:Action Potentials; D000818:Animals; D001665:Binding Sites; D017124:Conserved Sequence; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics; D009154:Mutation; D017434:Protein Structure, Tertiary; D051381:Rats; D017470:Receptors, Glutamate / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014981:Xenopus
chemical_list: D018690:Excitatory Amino Acid Agonists; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D011993:Recombinant Fusion Proteins; C108929:glutamate receptor delta 1; C107913:glutamate receptor delta 2