Still NAAG'ing After All These Years. The Continuing Pursuit of GCPII Inhibitors.

J. J. Vornov, K. R. Hollinger, P. F. Jackson, K. M. Wozniak, M. H. Farah, P. Majer, R. Rais, B. S. Slusher

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

Nearly two decades ago, Joe Coyle published a single-authored review with the provocative title, The Nagging Question of the Function of N-Acetylaspartylglutamate (Coyle, 1997). In this review, Coyle documented NAAG's localization to subpopulations of glutamatergic, cholinergic, GABAergic, and noradrenergic neurons, Ca2+-dependent release, mGlu3 receptor agonist and NMDA receptor antagonist activity, and cleavage by the glial enzyme glutamate carboxypeptidase II (GCPII). However, at the time of his review, NAAG's physiological function as a neurotransmitter remained elusive. Ironically his review was published months following the discovery of the first potent and selective GCPII inhibitor, 2-(phosphonomethyl)pentanedioc acid (2-PMPA) (Jackson et al., 1996). Over the ensuing decades, over a dozen independent laboratories used 2-PMPA and other GCPII inhibitors to elucidate two distinct neurotransmitter functions for NAAG. Under basal conditions, when GCPII activity is relatively low, intact NAAG dampens synaptic activity via presynaptic mGlu3 receptor activation and NMDA receptor blockade. However, under stimulated conditions, NAAG release and GCPII activity are enhanced resulting in excess glutamate generation, activating NMDA and other glutamate receptors, often pathologically. Diverse classes of GCPII inhibitors have been synthesized and shown to increase NAAG, decrease glutamate, and provide robust efficacy in many disease models wherein abnormal glutamatergic transmission is presumed pathogenic. In addition, over the past 20 years, basic questions regarding NAAG's synthesis, packaging into vesicles, and receptor selectivity profile have been eloquently elucidated. The purpose of this chapter is to summarize these advances and the promise of regulating NAAG metabolism through GCPII inhibition as a therapeutic strategy.

Original languageEnglish (US)
Title of host publicationNeuropsychopharmacology
Subtitle of host publicationA Tribute to Joseph T. Coyle, 2016
EditorsRobert Schwarcz
PublisherAcademic Press Inc.
Pages215-255
Number of pages41
ISBN (Print)9780128097458
DOIs
StatePublished - Jan 1 2016

Publication series

NameAdvances in Pharmacology
Volume76
ISSN (Print)1054-3589
ISSN (Electronic)1557-8925

Keywords

  • GCPII
  • Glutamate
  • MGlu3
  • NAAG
  • NAAG peptidase
  • NAALADase
  • NMDA
  • NR2A
  • NR2B

ASJC Scopus subject areas

  • Pharmacology

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  • Cite this

    Vornov, J. J., Hollinger, K. R., Jackson, P. F., Wozniak, K. M., Farah, M. H., Majer, P., Rais, R., & Slusher, B. S. (2016). Still NAAG'ing After All These Years. The Continuing Pursuit of GCPII Inhibitors. In R. Schwarcz (Ed.), Neuropsychopharmacology: A Tribute to Joseph T. Coyle, 2016 (pp. 215-255). (Advances in Pharmacology; Vol. 76). Academic Press Inc.. https://doi.org/10.1016/bs.apha.2016.01.007