The Good and Bad Sides of NAAG.

Why has such a small peptide been the source of controversy in neuroscience over the last 5 decades? Is N-acetyl-aspartyl-glutamate (NAAG) a neurotransmitter? Is NAAG located in neuronal tissue or in astrocytes? Is NAAG involved in neuropsychiatric and neurodegenerative disorders? Is NAAG therapeutically beneficial in the treatment of stroke or in initiating cascades of events leading to psychosis? After many years of intense research there is no clear consensus within the scientific community on how NAAG behaves in the brain. One of the major controversies about NAAG is its physiological action at N-methyl-d-aspartate (NMDA) receptors. While some researchers strongly argue that NAAG acts as a weak agonist at NMDA receptors, others have suggested that NAAG could behave as a potent antagonist. Published data from our laboratory demonstrate that the effect of NAAG on NMDA receptors could be influenced by a number of factors including the subcellular localization and subunit composition of NMDA receptors, as well as protons. In this chapter, we will summarize the knowledge of the literature on NAAG, however, we will place emphasis on our recently published data. More specifically, we have reported interesting findings on the effects of NAAG on NMDA receptors at synaptic and extrasynaptic sites using a pharmacological paradigm to distinguish the two populations of NMDA receptors. Additionally, we have evaluated the role of NAAG on GluN2A- and GluN2B-containing NMDA receptors using a HEK293 cell recombinant system. Finally, we have studied the effects of NAAG on GluN2A- and GluN2B-containing NMDA receptors in different extracellular pH conditions. We believe that our findings could potentially resolve some aspects of the debate regarding the role of NAAG at NMDA receptors.