title: Glutamate Stimulates Local Protein Synthesis in the Axons of Rat Cortical Neurons by Activating α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors and Metabotropic Glutamate Receptors.
abstract: Glutamate is the principal excitatory neurotransmitter in the mammalian CNS. By analyzing the metabolic incorporation of azidohomoalanine, a methionine analogue, in newly synthesized proteins, we find that glutamate treatments up-regulate protein translation not only in intact rat cortical neurons in culture but also in the axons emitting from cortical neurons before making synapses with target cells. The process by which glutamate stimulates local translation in axons begins with the binding of glutamate to the ionotropic AMPA receptors and metabotropic glutamate receptor 1 and members of group 2 metabotropic glutamate receptors on the plasma membrane. Subsequently, the activated mammalian target of rapamycin (mTOR) signaling pathway and the rise in Ca(2+), resulting from Ca(2+) influxes through calcium-permeable AMPA receptors, voltage-gated Ca(2+) channels, and transient receptor potential canonical channels, in axons stimulate the local translation machinery. For comparison, the enhancement effects of brain-derived neurotrophic factor (BDNF) on the local protein synthesis in cortical axons were also studied. The results indicate that Ca(2+) influxes via transient receptor potential canonical channels and activated the mTOR pathway in axons also mediate BDNF stimulation to local protein synthesis. However, glutamate- and BDNF-induced enhancements of translation in axons exhibit different kinetics. Moreover, Ca(2+) and mTOR signaling appear to play roles carrying different weights, respectively, in transducing glutamate- and BDNF-induced enhancements of axonal translation. Thus, our results indicate that exposure to transient increases of glutamate and more lasting increases of BDNF would stimulate local protein synthesis in migrating axons en route to their targets in the developing brain.
authors.affiliation: Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Hsu
authors.affiliation: Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Chung
authors.affiliation: Institute of Systems Neuroscience, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Chih-Yueh
authors.initials: CY
authors.lastname: Wu
authors.affiliation: Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Huei-Ing
authors.initials: HI
authors.lastname: Wu
authors.affiliation: Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Yu-Tao
authors.initials: YT
authors.lastname: Lee
authors.affiliation: Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: En-Chan
authors.initials: EC
authors.lastname: Chen
authors.affiliation: Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Weilun
authors.initials: W
authors.lastname: Fang
authors.affiliation: Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 300, Taiwan; Institute of Systems Neuroscience, National Tsing Hua University, Hsinchu 300, Taiwan; Institute of Nanoengineering and Microsystems, National Tsing Hua University, Hsinchu 300, Taiwan. Electronic address: ycchang@life.nthu.edu.tw.
authors.forename: Yen-Chung
authors.initials: YC
authors.lastname: Chang
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D007700:Kinetics; D061251:Primary Cell Culture; D014176:Protein Biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D015220:Calcium Channels; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D050916:TRPV Cation Channels; C506098:azidohomoalanine; C108822:metabotropic glutamate receptor 2; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D000409:Alanine
keywords: axon; glutamate; local translation; metabotropic glutamate receptor (mGluR); protein synthesis; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor, AMPAR)