title: 3-Aminoglutarate is a "silent" false transmitter for glutamate neurons.
abstract: Understanding the storage and release of the excitatory neurotransmitter, L-glutamate by synaptic vesicles has lagged behind receptor characterizations due to a lack of pharmacological agents. We report that the glutamate analog, 3-aminoglutarate (3-AG) is a "silent" false transmitter for glutamate neurons that may be a useful tool to study storage and release mechanisms. Like L-glutamate itself, 3-AG is a high-affinity substrate for both the plasma membrane (EAATs) and vesicular (vGLUT) glutamate transporters. As such, EAATs facilitate 3-AG entry into neuronal cytoplasm allowing 3-AG to compete with L-glutamate for transport into vesicles thus reducing glutamate content. In a synaptosomal preparation, 3-AG inhibited calcium-dependent endogenous L-glutamate release. Unlike L-glutamate, 3-AG had low affinity for both ionotropic (NMDA and AMPA) and G-protein coupled (mGlu1-8) receptors. Consequently, 3-AG behaves as a "silent" false transmitter that may be used in physiological experiments to probe synaptic vesicle storage and release mechanisms for L-glutamate. The companion paper by Wu et al. (2015) describes initial experiments that explore the effects of 3-AG on glutamate synaptic transmission under physiological and pathophysiological conditions.
authors.affiliation: Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, USA.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Foster
authors.affiliation: Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, USA.
authors.forename: June
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Runyan
authors.affiliation: Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Dinh
authors.affiliation: Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Venadas
authors.affiliation: Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, USA.
authors.forename: George R
authors.initials: GR
authors.lastname: Ehring
authors.affiliation: Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, USA. Electronic address: li_yongxin@allergan.com.
authors.forename: Yong-Xin
authors.initials: YX
authors.lastname: Li
authors.affiliation: Department of Biological Sciences, Allergan, Inc., 2525 Dupont Drive, Irvine, CA 92612, USA.
authors.forename: Ursula
authors.initials: U
authors.lastname: Staubli
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D050491:Glutamate Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D009865:Oocytes; D016548:Prosencephalon / Q000187:drug effects / Q000502:physiology; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D058468:Receptors, Ionotropic Glutamate / Q000378:metabolism; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D014981:Xenopus
chemical_list: D050491:Glutamate Plasma Membrane Transport Proteins; D005971:Glutamates; D018377:Neurotransmitter Agents; D043562:Receptors, G-Protein-Coupled; D058468:Receptors, Ionotropic Glutamate; C035260:3-aminoglutaric acid; D018698:Glutamic Acid; D002118:Calcium
keywords: False transmitter; Glutamate; Synaptic transmission; Synaptic vesicle; Transmitter release; Transport