N-methyl-D-aspartate receptor- and metabotropic glutamate receptor-dependent long-term depression are differentially regulated by the ubiquitin-proteasome system.
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 alpha-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.
Citri
Ami
A
Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94304-5552, USA.
Soler-Llavina
Gilberto
G
Bhattacharyya
Samarjit
S
Malenka
Robert C
RC
D000818:Animals; D000831:Animals, Newborn; D056547:CA1 Region, Hippocampal / Q000166:cytology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D004705:Endocytosis / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D046509:Tissue Culture Techniques; D025801:Ubiquitin / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D025801:Ubiquitin; D013779:Tetrodotoxin; D008734:Methoxyhydroxyphenylglycol; D046988:Proteasome Endopeptidase Complex; C010117:3,4-dihydroxyphenylglycol