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N ‐methyl‐ d ‐aspartate receptor‐ and metabotropic glutamate receptor‐dependent long‐term depression are differentially regulated by the ubiquitin‐proteasome system
Author(s) -
Citri Ami,
SolerLlavina Gilberto,
Bhattacharyya Samarjit,
Malenka Robert C.
Publication year - 2009
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/j.1460-9568.2009.06950.x
Subject(s) - metabotropic glutamate receptor 1 , metabotropic glutamate receptor 3 , metabotropic glutamate receptor 5 , metabotropic glutamate receptor , metabotropic glutamate receptor 6 , metabotropic glutamate receptor 4 , metabotropic glutamate receptor 2 , metabotropic glutamate receptor 7 , chemistry , glutamate receptor , metabotropic receptor , nmda receptor , microbiology and biotechnology , receptor , neuroscience , biochemistry , biology
Long‐term depression (LTD) in CA1 pyramidal neurons can be induced by activation of either N ‐methyl‐ d ‐aspartate receptors (NMDARs) or metabotropic glutamate receptors (mGluRs), both of which elicit changes in synaptic efficacy through α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate receptor (AMPAR) endocytosis. To address the role of the ubiquitin‐proteasome system in regulating AMPAR endocytosis during these forms of LTD, we examined the effects of pharmacological inhibitors of proteasomal degradation and protein ubiquitination on endocytosis of glutamate receptor 1 (GluR1) ‐containing AMPARs in dissociated rat hippocampal cultures as well as LTD of excitatory synaptic responses in acute rat hippocampal slices. Our findings suggest that the contribution of the ubiquitin‐proteasome system to NMDAR‐induced vs. mGluR‐induced AMPAR endocytosis and the consequent LTD differs significantly. NMDAR‐induced AMPAR endocytosis and LTD occur independently of proteasome function but appear to depend, at least in part, on ubiquitination. In contrast, mGluR‐induced AMPAR endocytosis and LTD are enhanced by inhibition of proteasomal degradation, as well as by the inhibitor of protein ubiquitination. Furthermore, the decay of mGluR‐induced membrane depolarization and Erk activation is delayed following inhibition of either ubiquitination or proteasomal degradation. These results suggest that, although NMDAR‐dependent LTD may utilize ubiquitin as a signal for AMPAR endocytosis, mGluR‐induced signaling and LTD are limited by a feedback mechanism that involves the ubiquitin‐proteasome system.