Abstract
Regulation of neuronal NMDA receptors (NMDARs) by group I metabotropic glutamate receptors (mGluRs) is known to play a critical role in synaptic transmission. The molecular mechanisms underlying mGluR1-mediated potentiation of NMDARs are as yet unclear. The present study shows that in Xenopus oocytes expressing recombinant receptors, activation of mGluR1 potentiates NMDA channel activity by recruitment of new channels to the plasma membrane via regulated exocytosis. Activation of mGluR1alpha induced (1) an increase in channel number times channel open probability, with no change in mean open time, unitary conductance, or reversal potential; (2) an increase in charge transfer in the presence of NMDA and the open channel blocker MK-801, indicating an increased number of functional NMDARs in the cell membrane; and (3) increased NR1 surface expression, as indicated by cell surface Western blots and immunofluorescence. Botulinum neurotoxin A or expression of a dominant negative mutant of synaptosomal associated protein of 25 kDa molelcular mass (SNAP-25) greatly reduced mGluR1alpha-mediated potentiation, indicating that receptor trafficking occurs via a SNAP-25-mediated form of soluble N-ethylmaleimide sensitive fusion protein attachment protein receptor-dependent exocytosis. Because group I mGluRs are localized to the perisynaptic region in juxtaposition to synaptic NMDARs at glutamatergic synapses in the hippocampus, mGluR-mediated insertion of NMDARs may play a role in synaptic transmission and plasticity, including long-term potentiation.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Blotting, Western
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Botulinum Toxins, Type A / pharmacology
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Cell Membrane / metabolism
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Cells, Cultured
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Cycloleucine / analogs & derivatives
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Cycloleucine / pharmacology
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Dizocilpine Maleate / pharmacology
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Excitatory Amino Acid Agonists / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Exocytosis / physiology
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Fluorescent Antibody Technique
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Ion Channel Gating / drug effects
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Ion Channel Gating / physiology
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Membrane Potentials / drug effects
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Membrane Proteins*
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N-Methylaspartate / metabolism
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N-Methylaspartate / pharmacology
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Nerve Tissue Proteins / biosynthesis
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / pharmacology
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Oocytes / cytology
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Oocytes / drug effects
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Oocytes / metabolism
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Patch-Clamp Techniques
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Protein Transport / drug effects
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Protein Transport / physiology
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Rats
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Receptors, Metabotropic Glutamate / agonists
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Receptors, Metabotropic Glutamate / genetics
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Receptors, Metabotropic Glutamate / metabolism*
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Receptors, N-Methyl-D-Aspartate / genetics
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Receptors, N-Methyl-D-Aspartate / metabolism*
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Synaptosomal-Associated Protein 25
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Transfection
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Xenopus
Substances
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Excitatory Amino Acid Agonists
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Excitatory Amino Acid Antagonists
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Membrane Proteins
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NR1 NMDA receptor
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NR2A NMDA receptor
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Nerve Tissue Proteins
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Receptors, Metabotropic Glutamate
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Receptors, N-Methyl-D-Aspartate
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Snap25 protein, rat
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Synaptosomal-Associated Protein 25
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metabotropic glutamate receptor type 1
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Cycloleucine
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1-amino-1,3-dicarboxycyclopentane
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N-Methylaspartate
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Dizocilpine Maleate
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Botulinum Toxins, Type A