mGluR-dependent long-term depression is associated with increased phosphorylation of S6 and synthesis of elongation factor 1A but remains expressed in S6K-deficient mice.
Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) in the hippocampus requires rapid protein synthesis, which suggests that mGluR activation is coupled to signaling pathways that regulate translation. Herein, we have investigated the signaling pathways that couple group I mGluRs to ribosomal S6 protein phosphorylation and 5'oligopyrimidine tract (5'TOP)-encoded protein synthesis during mGluR-LTD. We found that mGluR-LTD was associated with increased phosphorylation of p70S6 kinase (S6K1) and S6, as well as the synthesis of the 5'TOP-encoded protein elongation factor 1A (EF1A). Moreover, we found that LTD-associated increases in S6K1 phosphorylation, S6 phosphorylation, and levels of EF1A were sensitive to inhibitors of phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), and extracellular signal-regulated kinase (ERK). However, mGluR-LTD was normal in S6K1 knockout mice and enhanced in both S6K2 knockout mice and S6K1/S6K2 double knockout mice. In addition, we observed that LTD-associated increases in S6 phosphorylation were still increased in S6K1- and S6K2-deficient mice, whereas basal levels of EF1A were abnormally elevated. Taken together, these findings indicate that mGluR-LTD is associated with PI3K-, mTOR-, and ERK-dependent alterations in the phosphorylation of S6 and S6K. Our data also suggest that S6Ks are not required for the expression of mGluR-LTD and that the synthesis of 5'TOP-encoded proteins is independent of S6Ks during mGluR-LTD.
Antion
Marcia D
MD
Center for Neural Science, New York University, 4 Washington Place, Room 809, New York, NY 10003, USA.
Hou
Lingfei
L
Wong
Helen
H
Hoeffer
Charles A
CA
Klann
Eric
E
D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006624:Hippocampus / Q000502:physiology; D066298:In Vitro Techniques; D036881:Long-Term Synaptic Depression; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020648:Peptide Elongation Factor 1 / Q000096:biosynthesis*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D038641:RNA 5' Terminal Oligopyrimidine Sequence; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D048049:Extracellular Signal-Regulated MAP Kinases; D020648:Peptide Elongation Factor 1; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D018094:Receptors, Metabotropic Glutamate; D019893:Ribosomal Protein S6 Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse