Abstract
Ionotropic glutamate receptors principally mediate fast excitatory transmission in the brain. Among the three classes of ionotropic glutamate receptors, kainate receptors (KARs) have a unique brain distribution, which has been historically defined by (3)H-radiolabeled kainate binding. Compared with recombinant KARs expressed in heterologous cells, synaptic KARs exhibit characteristically slow rise-time and decay kinetics. However, the mechanisms responsible for these distinct KAR properties remain unclear. We found that both the high-affinity binding pattern in the mouse brain and the channel properties of native KARs are determined by the KAR auxiliary subunit Neto1. Through modulation of agonist binding affinity and off-kinetics of KARs, but not trafficking of KARs, Neto1 determined both the KAR high-affinity binding pattern and the distinctively slow kinetics of postsynaptic KARs. By regulating KAR excitatory postsynaptic current kinetics, Neto1 can control synaptic temporal summation, spike generation and fidelity.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Biophysical Phenomena / drug effects
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Biophysical Phenomena / genetics
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Biophysics
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CA1 Region, Hippocampal / cytology
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CA1 Region, Hippocampal / metabolism*
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Cell Line, Transformed
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Cerebellum / cytology
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Cerebellum / metabolism*
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Disks Large Homolog 4 Protein
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Dizocilpine Maleate / pharmacology
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Dose-Response Relationship, Drug
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Drug Interactions
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Electric Stimulation / methods
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Excitatory Amino Acid Agonists / pharmacokinetics
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Excitatory Amino Acid Agonists / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / genetics
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Green Fluorescent Proteins / genetics
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Guanylate Kinases
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Humans
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Immunoprecipitation
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In Vitro Techniques
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Intracellular Signaling Peptides and Proteins / metabolism
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Kainic Acid / pharmacokinetics
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Kainic Acid / pharmacology
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LDL-Receptor Related Proteins
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Lipoproteins, LDL / deficiency
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Lipoproteins, LDL / metabolism*
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Membrane Potentials / drug effects
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Membrane Potentials / genetics
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Membrane Proteins / deficiency
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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Mice, Knockout
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Neurons / classification
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Neurons / drug effects
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Neurons / physiology
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Patch-Clamp Techniques / methods
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Presynaptic Terminals / drug effects
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Presynaptic Terminals / metabolism
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Protein Binding / drug effects
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Protein Subunits / genetics
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Protein Subunits / metabolism
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Receptors, Kainic Acid / classification
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Receptors, Kainic Acid / deficiency
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Receptors, Kainic Acid / physiology*
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Receptors, N-Methyl-D-Aspartate
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Synaptophysin / metabolism
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Transfection / methods
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Tritium / pharmacokinetics
Substances
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Disks Large Homolog 4 Protein
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Dlg4 protein, mouse
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Excitatory Amino Acid Agonists
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Excitatory Amino Acid Antagonists
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Intracellular Signaling Peptides and Proteins
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LDL-Receptor Related Proteins
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Lipoproteins, LDL
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Membrane Proteins
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NETO2 protein, mouse
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Neto1 protein, mouse
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Protein Subunits
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Receptors, Kainic Acid
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Receptors, N-Methyl-D-Aspartate
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Synaptophysin
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Tritium
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Green Fluorescent Proteins
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Dizocilpine Maleate
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Guanylate Kinases
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Kainic Acid