mGluR1/5-dependent long-term depression requires the regulated ectodomain cleavage of neuronal pentraxin NPR by TACE.
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.
Cho
Richard W
RW
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Park
Joo Min
JM
Wolff
Steffen B E
SB
Xu
Desheng
D
Hopf
Carsten
C
Kim
Jin-Ah
JA
Reddy
Radhika C
RC
Petralia
Ronald S
RS
Perin
Mark S
MS
Linden
David J
DJ
Worley
Paul F
PF
D051722:ADAM Proteins / Q000378:metabolism / Q000494:pharmacology*; D000072198:ADAM17 Protein; D000818:Animals; D000831:Animals, Newborn; D002097:C-Reactive Protein / Q000172:deficiency; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D004622:Embryo, Mammalian; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D017434:Protein Structure, Tertiary / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D014162:Transfection; D000099153:Pentraxins
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D002097:C-Reactive Protein; D018683:Excitatory Amino Acid Agents; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D018094:Receptors, Metabotropic Glutamate; D000099153:Pentraxins; C104077:metabotropic glutamate receptor type 1; C107687:neuronal pentraxin receptor; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse