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The neuropeptide N-Acetylaspartylglutamate (NAAG) is the third-most-prevalent neurotransmitter in the mammalian nervous system. NAAG consists of N-acetylaspartate (NAA) and glutamate coupled via a peptide bond. NAAG was discovered as a nervous system-specific peptide in 1965 by Curatolo and colleagues but was not extensively studied for nearly 20 years. It meets the criteria for a neurotransmitter, including being concentrated in neurons, packed in synaptic vesicles, released in a calcium-dependent manner, and hydrolyzed in the synaptic space by enzymatic activity. NAAG activates a specific receptor, the metabotropic glutamate receptor type 3. It is synthesized enzymatically from its two precursors and catabolized by NAAG peptidases in the synapse. The inhibition of the latter enzymes has potentially important therapeutic effects in animal models of several neurologic conditions and disorders.
According to one publication, NAAG can be differentiated from NAA in vivo by MR spectroscopy at 3 Tesla.
Additional recommended knowledge
After its discovery in 1965, NAAG was disregarded as a neurotransmitter for a couple reasons. First, neuropeptides were not considered neurotransmitters until years later. Second, it did not seem to directly affect membrane potential, so it was classified as a metabolic intermediate, an idea that has never been further explored. However, once the endogenous opioids were discovered, the importance of brain peptides became more clear. While there is considerable controversy as to the ability of NAAG to interact with NMDA receptors in a manner relevant to physiology, its primary receptor is clearly the mGluR3. Its interaction with the mGluR3 causes an activation of G proteins that reduce the concentration of the second messengers cAMP and cGMP in the both nerve cells and glia. This can lead to several changes in the cellular activity, including regulation of gene expression, reduction in the release of transmitter, and inhibition of long-term potentiation.
“NAAG synthetase” activity mediates the biosynthesis of NAAG from glutamate and NAA, but little about the mechanism or regulation of this enzyme is known and no NAAG synthetase activity has been isolated in cell-free preprations. Since other neuropeptides and nearly all vertebrate peptides are synthesized by post-translational processing, NAAG synthtase activity is relatively unique. As with NAA, the synthesis of NAAG is primarily restricted to neurons, although glial cells also contain and synthesize this peptide. In vitro, NAAG synthesis appears to be regulated by the availability of its precursor, NAA. In addition, during differentiation of neuroblastoma cells, it has been shown that a Protein kinase A (PKA) activator will increase the quantity of NAAG while a Protein kinase C (PKC) activator will decrease its concentration. This suggests that PKA and PKC have opposing regulatory effects on the NAAG synthetase enzyme.
The catabolism of NAAG via NAAG peptidase activity was first discovered by Riveros and Orrego in 1984. Two enzymes with NAAG peptidase activity have since been cloned (glutamate carboxypeptidase II and glutamate carboxypeptidase III), which mediate the hydrolysis of NAAG to NAA and glutamate. Inhibition of these peptidase activities has become important in the area in neurology, as the inhibition of these enzymes can produce several potentially significant therapeutic effects. There are two main types of inhibitors of this enzyme: compounds related to 2-(phosphonomethyl)pentanedioic acid (2-PMPA) and urea-based analogs of NAAG, including ZJ43, ZJ17, and ZJ11. The inhibition of NAAG peptidase has therapeutic potential in a number of different diseases and disorders. In rat models, ZJ43 and 2-PMPA reduce perception of inflammatory and neuropathic pain when administered systemically, intracerebrally, or locally, suggesting that NAAG modulates neurotrasmission in pain circuits via mGlu3 receptors. The inhibition of NAAG hydrolysis increases the concentration of NAAG in the synaptic space analygous to the effects of SSRIs in increasing the concentration of serotonin. This elevated NAAG gives greater activation of presynaptic mGluR3 receptors, which decrease transmitter (glutamate) release in the pain signaling pathways of the spinal cord and brain. In the case of traumatic brain injury, the injection of a NAAG peptidase inhibitor reduces neuron and astrocyte death in the hippocampus nearest the site of the injury. In a mouse model of amyotrophic lateral sclerosis (ALS), the chronic inhibition of NAAG peptidase activity delayed the onset of ALS symptoms and slowed the progress of the neuronal death. To model schizophrenia, animals were injected with phencyclidine (PCP) and, therefore, exhibited symptoms of the disorder, such as social withdrawal and motor responses. Upon injection with ZJ43, these behaviors were decreased, suggesting that an increase in NAAG in the synapse - and its subsequent activation of mGluR3 receptors - has potential as a novel co-therapy for schizophernia. In all of these cases, NAAG peptidase inhibition has been successful in reducing the adverse effects in these disorders. Future research focuses on defining more precisely the role of NAAG in pain perception, brain injury, and schizophrenia while developing NAAG peptidase inhibitors with even greater ability to cross the blood brain barrier.
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "N-Acetylaspartylglutamate". A list of authors is available in Wikipedia.|