title: Novel Functional Properties of Drosophila CNS Glutamate Receptors.
abstract: Phylogenetic analysis reveals AMPA, kainate, and NMDA receptor families in insect genomes, suggesting conserved functional properties corresponding to their vertebrate counterparts. However, heterologous expression of the Drosophila kainate receptor DKaiR1D and the AMPA receptor DGluR1A revealed novel ligand selectivity at odds with the classification used for vertebrate glutamate receptor ion channels (iGluRs). DKaiR1D forms a rapidly activating and desensitizing receptor that is inhibited by both NMDA and the NMDA receptor antagonist AP5; crystallization of the KaiR1D ligand-binding domain reveals that these ligands stabilize open cleft conformations, explaining their action as antagonists. Surprisingly, the AMPA receptor DGluR1A shows weak activation by its namesake agonist AMPA and also by quisqualate. Crystallization of the DGluR1A ligand-binding domain reveals amino acid exchanges that interfere with binding of these ligands. The unexpected ligand-binding profiles of insect iGluRs allows classical tools to be used in novel approaches for the study of synaptic regulation. VIDEO ABSTRACT.
authors.affiliation: Program in Cellular Regulation and Metabolism, NICHD, NIH, Bethesda, MD 20892, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, NICHD, NIH, Bethesda, MD 20892, USA.
authors.forename: Poorva
authors.initials: P
authors.lastname: Dharkar
authors.affiliation: Program in Cellular Regulation and Metabolism, NICHD, NIH, Bethesda, MD 20892, USA.
authors.forename: Tae-Hee
authors.initials: TH
authors.lastname: Han
authors.affiliation: Program in Cellular Regulation and Metabolism, NICHD, NIH, Bethesda, MD 20892, USA.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Serpe
authors.affiliation: Program in Cellular Regulation and Metabolism, NICHD, NIH, Bethesda, MD 20892, USA. Electronic address: leechih@mail.nih.gov.
authors.forename: Chi-Hon
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, NICHD, NIH, Bethesda, MD 20892, USA. Electronic address: mayerm@mail.nih.gov.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Mayer
mesh_terms: D000818:Animals; D015220:Calcium Channels; D002490:Central Nervous System / Q000378:metabolism*; D003461:Crystallography; D004331:Drosophila melanogaster; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D016202:N-Methylaspartate / Q000494:pharmacology; D016318:Quisqualic Acid / Q000494:pharmacology; D018091:Receptors, AMPA / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D016202:N-Methylaspartate; D016318:Quisqualic Acid; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
keywords: AP5; Drosophila; NMDA; crystal structures; glutamate receptors