title: AMP-activated protein kinase counteracts brain-derived neurotrophic factor-induced mammalian target of rapamycin complex 1 signaling in neurons.
abstract: Growth factors and nutrients, such as amino acids and glucose, regulate mammalian target of rapamycin complex 1 (mTORC1) signaling and subsequent translational control in a coordinated manner. Brain-derived neurotrophic factor (BDNF), the most prominent neurotrophic factor in the brain, activates mTORC1 and induces phosphorylation of its target, p70S6 kinase (p70S6K), at Thr389 in neurons. BDNF also increases mammalian target of rapamycin-dependent novel protein synthesis in neurons. Here, we report that BDNF-induced p70S6K activation is dependent on glucose, but not amino acids, sufficiency in cultured cortical neurons. AMP-activated protein kinase (AMPK) is the molecular background to this specific nutrient dependency. Activation of AMPK, which is induced by glucose deprivation, treatment with pharmacological agents such as 2-deoxy-D-glucose, metformin, and 5-aminoimidazole-4-carboxamide ribonucleoside or forced expression of a constitutively active AMPKα subunit, counteracts BDNF-induced phosphorylation of p70S6K and enhanced protein synthesis in cortical neurons. These results indicate that AMPK inhibits the effects of BDNF on mTORC1-mediated translation in neurons.
authors.affiliation: Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan; Department of Neurobiology and Behavior, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Ishizuka
authors.forename: Naomasa
authors.initials: N
authors.lastname: Kakiya
authors.forename: Lee A
authors.initials: LA
authors.lastname: Witters
authors.forename: Noriko
authors.initials: N
authors.lastname: Oshiro
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Shirao
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nawa
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takei
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D018274:Electroporation; D005347:Fibroblasts / Q000378:metabolism; D005947:Glucose / Q000172:deficiency / Q000502:physiology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin / Q000494:pharmacology; D008715:Methionine / Q000378:metabolism; D046912:Multiprotein Complexes / Q000502:physiology*; D009474:Neurons / Q000187:drug effects*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D007004:Hypoglycemic Agents; D046912:Multiprotein Complexes; D008687:Metformin; D003847:Deoxyglucose; D008715:Methionine; D000076222:Mechanistic Target of Rapamycin Complex 1; D051058:Oncogene Protein v-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: AMPK; BDNF; mTOR; neuron; protein synthesis; translation