Still NAAG'ing After All These Years: The Continuing Pursuit of GCPII Inhibitors.
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, Ca(2+)-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.
Johns Hopkins School of Medicine, Baltimore, MD, United States; Medpace, Cincinnati, OH, United States.
J J
JJ
Vornov
Johns Hopkins School of Medicine, Baltimore, MD, United States.
K R
KR
Hollinger
Janssen Pharmaceuticals, San Diego, CA, United States.
P F
PF
Jackson
Johns Hopkins School of Medicine, Baltimore, MD, United States.
K M
KM
Wozniak
Johns Hopkins School of Medicine, Baltimore, MD, United States.
M H
MH
Farah
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
P
P
Majer
Johns Hopkins School of Medicine, Baltimore, MD, United States.
R
R
Rais
Johns Hopkins School of Medicine, Baltimore, MD, United States. Electronic address: bslusher@jhmi.edu.
B S
BS
Slusher
D000818:Animals; D000954:Antigens, Surface; D004151:Dipeptides / Q000378:metabolism*; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D009457:Neuroglia / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism
D000954:Antigens, Surface; D004151:Dipeptides; D018377:Neurotransmitter Agents; C027172:isospaglumic acid; D018698:Glutamic Acid; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
GCPII; Glutamate; NAAG; NAAG peptidase; NAALADase; NMDA; NR2A; NR2B; mGlu3