Abstract
N-acetyl-aspartyl-glutamate (NAAG) is the most abundant dipeptide in the brain, where it acts as a neuromodulator of glutamatergic synapses by activating presynaptic metabotropic glutamate receptor 3 (mGluR3). Recent data suggest that NAAG is selectively localized to postsynaptic dendrites in glutamatergic synapses and that it works as a retrograde neurotransmitter. NAAG is released in response to glutamate and provides the postsynaptic neuron with a feedback mechanisms to inhibit excessive glutamate signaling. A key regulator of synaptically available NAAG is rapid degradation by the extracellular enzyme glutamate carboxypeptidase II (GCPII). Increasing endogenous NAAG—for instance by inhibiting GCPII—is a promising treatment option for many brain disorders where glutamatergic excitotoxicity plays a role. The main effect of NAAG occurs through increased mGluR3 activation and thereby reduced glutamate release. In the present review, we summarize the transmitter role of NAAG and discuss the involvement of NAAG in normal brain physiology. We further present the suggested roles of NAAG in various neurological and psychiatric diseases and discuss the therapeutic potential of strategies aiming to enhance NAAG levels.
Highlights
Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, The Faculty of Mathematics and Natural Sciences, University of Oslo, 1068 Oslo, Norway
N-acetyl-aspartyl-glutamate (NAAG) is a N-acetylated dipeptide selectively localized to brain, where it is present in μM–mM concentrations [1]
The release of NAAG is largely dependent on the release of glutamate, but we have previously presented evidence for a basal release of NAAG even at very low glutamate signaling levels [21]
Summary
N-acetyl-aspartyl-glutamate (NAAG) is a N-acetylated dipeptide selectively localized to brain, where it is present in μM–mM concentrations [1]. 15-fold (to 2.0 μM) in response to experimental traumatic brain injury (TBI) [5] These basal data are supported by the baseline microdialysis data from the prefrontal cortex (0.10 μM) and the nucleus accumbens (0.088 μM) reported by Zuo and colleagues [6]. The activation of the presynaptic metabotropic glutamate receptor 3 (mGluR3) represents one such strategy and can be achieved by increasing the levels of the endogenous mGluR3 agonist NAAG. We further present the suggested roles of NAAG in various neurological and psychiatric diseases and discuss the therapeutic potential of strategies aiming to enhance NAAG levels
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