title: Resveratrol up-regulates AMPA receptor expression via AMP-activated protein kinase-mediated protein translation.
abstract: Resveratrol is a phytoalexin that confers overall health benefits including positive regulation in brain function such as learning and cognition. However, whether and how resveratrol affects synaptic activity remains largely unknown. α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are glutamatergic receptors that mediate the majority of fast excitatory transmission and synaptic plasticity, and thus play a critical role in higher brain functions, including learning and memory. We find that in rat primary neurons, resveratrol can rapidly increase AMPAR protein level, AMPAR synaptic accumulation and the strength of excitatory synaptic transmission. The resveratrol effect on AMPAR protein expression is independent of sirtuin 1 (SIRT1), the conventional downstream target of resveratrol, but rather is mediated by AMP-activated protein kinase (AMPK) and subsequent downstream phosphoinositide 3-kinase (PI3K)/Akt signaling. Application of the AMPK specific activator 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) mimics the effects of resveratrol on both signaling and AMPAR expression. The resveratrol-induced increase in AMPAR expression results from elevated protein synthesis via regulation of the eukaryotic initiation factor (eIF) 4E/4G complex. Disruption of the translation initiation complex completely blocks resveratrol-dependent AMPAR up-regulation. These findings indicate that resveratrol may regulate brain function through facilitation of AMPAR biogenesis and synaptic transmission.
authors: Department of Biology, Boston University, Boston, MA 02215, USA.
authors: Guan
authors: G
authors: Wang
authors: Department of Biology, Boston University, Boston, MA 02215, USA.
authors: Stephen
authors: S
authors: Amato
authors: Department of Biology, Boston University, Boston, MA 02215, USA.
authors: James
authors: J
authors: Gilbert
authors: Department of Biology, Boston University, Boston, MA 02215, USA. Electronic address: hman@bu.edu.
authors: Heng-Ye
authors: HY
authors: Man
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D000077185:Resveratrol; D012265:Ribonucleotides / Q000494:pharmacology; D056564:Sirtuin 1 / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; D039561:Eukaryotic Initiation Factor-4E; D039603:Eukaryotic Initiation Factor-4G; D018683:Excitatory Amino Acid Agents; D018091:Receptors, AMPA; D012265:Ribonucleotides; D013267:Stilbenes; D000620:Aminoimidazole Carboxamide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; C031143:AICA ribonucleotide; D000077185:Resveratrol
keywords: AMP-activated protein kinase (AMPK); Phosphoinositide 3-kinase (PI3K); Protein translation; Resveratrol; Sirtuin 1 (SIRT1); α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPA receptor, AMPAR)