Abstract
Matrix metalloproteases (MMPs) play a role in remodeling the extracellular matrix during brain development and have been implicated in synaptic plasticity. Here, we report that a member of the neuronal pentraxin (NP) family, neuronal pentraxin receptor (NPR), undergoes regulated cleavage by the MMP tumor necrosis factor-alpha converting enzyme (TACE). NPR is enriched at excitatory synapses where it associates with AMPA-type glutamate receptors (AMPAR) and enhances synaptogenesis. However, in response to activation of group 1 mGluRs (mGluR1/5), TACE cleaves NPR and releases the pentraxin domain from its N-terminal transmembrane domain. Cleaved NPR rapidly accumulates in endosomes where it colocalizes with AMPAR. This process is necessary for mGluR1/5-dependent LTD in hippocampal and cerebellar synapses. These observations suggest that cleaved NPR functions to "capture" AMPAR for endocytosis and reveal a bifunctional role of NPs in both synapse strengthening and weakening.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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ADAM Proteins / metabolism
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ADAM Proteins / pharmacology*
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ADAM17 Protein
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Animals
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Animals, Newborn
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C-Reactive Protein / deficiency
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Cells, Cultured
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Cerebellum / cytology
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Embryo, Mammalian
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Excitatory Amino Acid Agents / pharmacology
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Hippocampus / cytology
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Humans
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Inhibitory Postsynaptic Potentials / drug effects
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Inhibitory Postsynaptic Potentials / physiology*
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Inhibitory Postsynaptic Potentials / radiation effects
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Mice
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Mice, Knockout
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Nerve Tissue Proteins / deficiency
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Neuronal Plasticity / drug effects
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Neuronal Plasticity / physiology
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Neuronal Plasticity / radiation effects
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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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Protein Structure, Tertiary / physiology
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RNA, Small Interfering / pharmacology
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Receptors, Cell Surface / chemistry
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Receptors, Cell Surface / deficiency
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Receptors, Cell Surface / metabolism*
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Receptors, Metabotropic Glutamate / physiology*
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Transfection
Substances
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Excitatory Amino Acid Agents
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Nerve Tissue Proteins
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RNA, Small Interfering
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Receptors, Cell Surface
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Receptors, Metabotropic Glutamate
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metabotropic glutamate receptor type 1
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neuronal pentraxin
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neuronal pentraxin receptor
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C-Reactive Protein
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ADAM Proteins
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ADAM17 Protein
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ADAM17 protein, human
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Adam17 protein, mouse