Distinct functions of kainate receptors in the brain are determined by the auxiliary subunit Neto1

Nat Neurosci. 2011 May 29;14(7):866-73. doi: 10.1038/nn.2837.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Biophysical Phenomena / drug effects
  • Biophysical Phenomena / genetics
  • Biophysics
  • CA1 Region, Hippocampal / cytology
  • CA1 Region, Hippocampal / metabolism*
  • Cell Line, Transformed
  • Cerebellum / cytology
  • Cerebellum / metabolism*
  • Disks Large Homolog 4 Protein
  • Dizocilpine Maleate / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Electric Stimulation / methods
  • Excitatory Amino Acid Agonists / pharmacokinetics
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Green Fluorescent Proteins / genetics
  • Guanylate Kinases
  • Humans
  • Immunoprecipitation
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kainic Acid / pharmacokinetics
  • Kainic Acid / pharmacology
  • LDL-Receptor Related Proteins
  • Lipoproteins, LDL / deficiency
  • Lipoproteins, LDL / metabolism*
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Neurons / classification
  • Neurons / drug effects
  • Neurons / physiology
  • Patch-Clamp Techniques / methods
  • Presynaptic Terminals / drug effects
  • Presynaptic Terminals / metabolism
  • Protein Binding / drug effects
  • Protein Subunits / genetics
  • Protein Subunits / metabolism
  • Receptors, Kainic Acid / classification
  • Receptors, Kainic Acid / deficiency
  • Receptors, Kainic Acid / physiology*
  • Receptors, N-Methyl-D-Aspartate
  • Synaptophysin / metabolism
  • Transfection / methods
  • Tritium / pharmacokinetics

Substances

  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Intracellular Signaling Peptides and Proteins
  • LDL-Receptor Related Proteins
  • Lipoproteins, LDL
  • Membrane Proteins
  • NETO2 protein, mouse
  • Neto1 protein, mouse
  • Protein Subunits
  • Receptors, Kainic Acid
  • Receptors, N-Methyl-D-Aspartate
  • Synaptophysin
  • Tritium
  • Green Fluorescent Proteins
  • Dizocilpine Maleate
  • Guanylate Kinases
  • Kainic Acid