title: Dual regulation of fragile X mental retardation protein by group I metabotropic glutamate receptors controls translation-dependent epileptogenesis in the hippocampus.
abstract: Group I metabotropic glutamate receptors (mGluRs) stimulation activates translation-dependent epileptogenesis in the hippocampus. This translation is regulated by repressors, including BC1 RNA and fragile X mental retardation protein (FMRP). Recent data indicate that group I mGluR stimulation exerts bidirectional control over FMRP level by activating translation and ubiquitin-proteasome system (UPS)-dependent proteolysis for the up- and downregulation of the protein, respectively. At present, the temporal relationship of translation and proteolysis on FMRP and their interplay for group I mGluR-mediated translation and epileptogenesis are unknown. We addressed these issues by using mouse hippocampal slices. Agonist [(S)-3,5-dihydroxyphenylglycine (DHPG)] stimulation of group I mGluRs caused a biphasic change in FMRP level. An initial decrease (within 10 min) was followed by an increase at 30 min. When slices were pretreated with translation inhibitor (anisomycin or cycloheximide), group I mGluRs elicited a sustained decrease in FMRP. This decrease was prevented by a proteasome inhibitor [Z-Leu-Leu-Leu-CHO (MG-132)]. When slices were pretreated with MG-132 alone, DHPG no longer elicited any change in FMRP. MG-132 also suppressed increase in other proteins, including postsynaptic density-95 and α-calcium/calmodulin-dependent protein kinase II, normally elicited by group I mGluR stimulation. Physiological experiments showed that proteasome inhibitor suppressed group I mGluR-induced prolonged synchronized discharges. However, proteasome inhibitor did not affect group I mGluR-induced prolonged synchronized discharges in Fmr1(-/-) preparations, where functional FMRP is absent. The results suggest that constitutive FMRP in hippocampal cells acts as a brake on group I mGluR-mediated translation and epileptogenesis. FMRP downregulation via UPS removes this brake enabling group I mGluR-mediated translation and epileptogenesis.
authors.affiliation: The Robert F. Furchgott Center for Neural and Behavioral Science, and Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA.
authors.forename: Wangfa
authors.initials: W
authors.lastname: Zhao
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Chuang
authors.forename: Riccardo
authors.initials: R
authors.lastname: Bianchi
authors.forename: Robert K S
authors.initials: RK
authors.lastname: Wong
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000096:biosynthesis; D000076122:Disks Large Homolog 4 Protein; D004827:Epilepsy / Q000378:metabolism* / Q000503:physiopathology; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000096:biosynthesis* / Q000235:genetics; D051528:Guanylate Kinases; D006624:Hippocampus / Q000378:metabolism* / Q000503:physiopathology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D014176:Protein Biosynthesis; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000502:physiology*
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000076122:Disks Large Homolog 4 Protein; D051860:Fragile X Messenger Ribonucleoprotein 1; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018094:Receptors, Metabotropic Glutamate; C501447:Dlg4 protein, mouse; C497684:Fmr1 protein, mouse; C517671:Camk2a protein, mouse