title: Advances in understanding the peptide neurotransmitter NAAG and appearance of a new member of the NAAG neuropeptide family.
abstract: A substantial body of data was reported between 1984 and 2000 demonstrating that the neuropeptide N-acetylaspartylglutamate (NAAG) not only functions as a neurotransmitter but also is the third most prevalent transmitter in the mammalian nervous system behind glutamate and GABA. By 2005, this conclusion was validated further through a series of studies in vivo and in vitro. The primary enzyme responsible for the inactivation of NAAG following its synaptic release had been cloned, characterized and knocked out. Potent inhibitors of this enzyme were developed and their efficacy has been extensively studied in a series of animal models of clinical conditions, including stroke, peripheral neuropathy, traumatic brain injury, inflammatory and neuropathic pain, cocaine addiction, and schizophrenia. Considerable progress also has been made in defining further the mechanism of action of these peptidase inhibitors in elevating synaptic levels of NAAG with the consequent inhibition of transmitter release via the activation of pre-synaptic metabotropic glutamate receptor 3 by this peptide. Very recent discoveries include identification of two different nervous system enzymes that mediate the synthesis of NAAG from N-acetylaspartate and glutamate and the finding that one of these enzymes also mediates the synthesis of a second member of the NAAG family of neuropeptides, N-acetylaspartylglutamylglutamate.
authors.affiliation: Department of Biology, Georgetown University, Washington, District of Columbia 20057, USA. nealej@georgetown.edu
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Neale
authors.forename: Rafal T
authors.initials: RT
authors.lastname: Olszewski
authors.forename: Daiying
authors.initials: D
authors.lastname: Zuo
authors.forename: Karolina J
authors.initials: KJ
authors.lastname: Janczura
authors.forename: Caterina P
authors.initials: CP
authors.lastname: Profaci
authors.forename: Kaleen M
authors.initials: KM
authors.lastname: Lavin
authors.forename: John C
authors.initials: JC
authors.lastname: Madore
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bzdega
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D001930:Brain Injuries / Q000188:drug therapy; D004151:Dipeptides / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D009437:Neuralgia / Q000188:drug therapy; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy; D019966:Substance-Related Disorders / Q000628:therapy
chemical_list: D004151:Dipeptides; C561047:N-acetyl-aspartyl-glutamyl-glutamic acid; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D011480:Protease Inhibitors; C027172:isospaglumic acid; D043425:Glutamate Carboxypeptidase II