N-Acetylaspartylglutamate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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 colleaguesTemplate:Ref N 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.
Under the INN spaglumic acid, NAAG is used as an antiallergic medication in eye drops and nasal preparations.
Research history
After its discovery in 1965, NAAG was disregarded as a neurotransmitter for several reasons. First, neuropeptides were not considered neurotransmitters until years later. Secondly, it did not originally seem to directly affect membrane potential, so it was classified as a metabolic intermediate, an idea which 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 physiologically relevant manner, 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 messengerscAMPand 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 inhibiting long term potentiation.Template:Ref NTemplate:Ref N
Biosynthesis
“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. Like 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.Template:Ref NTemplate:Ref N
Catabolism
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 III). They 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 give greater activation of presynaptic mGluR3 receptors which decrease transmitter (glutamate) release in the pathways that pain signally 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.Template:Ref NTemplate:Ref NTemplate:Ref NTemplate:Ref NTemplate:Ref N
References
- Template:Note NCURATOLO A, D ARCANGELO P, LINO A, BRANCATI A (1965). "DISTRIBUTION OF N-ACETYL-ASPARTIC AND N-ACETYL-ASPARTYL-GLUTAMIC ACIDS IN NERVOUS TISSUE". J. Neurochem. 12: 339–42. PMID 14340686.
- Template:Note NCoyle, J.T. "The nagging question of the function of N-acetylaspartylglutamate." Neurobiology of Disease 4(1997): 231-8.
- Template:Note NNeale, J.H., Bzdega, T., Wroblewska, B., "N-Acetylaspartylglutamate: The Most Abundant Peptide Neurotransmitter in the Mammalian Central Nervous System." Journal of Neurochemistry 75(2000): 443-452. PMID 10899918 free full text
- Template:Note NGehl, Laura, Omar Saab, Tomasz Bzdega, Barbara Wroblewska and Joseph Neale. "Biosynthesis of NAAG by an enzyme-mediate process in rat central nervous neurons and glia." Journal of Neurochemistry 90(2004): 989-997.
- Template:Note NArun, P., Madhavarao, C.N., Moffett, J.R., Namboodiri, M.A.A., "Regulation of N-acetylaspartate and N-acetylaspartylglutamate biosynthesis by protein kinase activators." Journal of Neurochemistry 98(2006): 2034-2042.
- Template:Note NRiveros, N.; Orrego, F. "A study of possible excitatory effects of N-acetylaspartylglutamate in different in vivo and in vitro brain preparations." Brain Research 299(1984):393-395.
- Template:Note NYamamoto, T., Saito, O., Aoe, T., Bartolozzi, A., Sarva, J., Kozikowski, A., Wroblewska, B., Bzdega, T., and Neale, J. H. "Local Administration of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibitors Is Analgesic in Peripheral Pain," European Journal of Neuroscience 25(2007):147-158.
- Template:Note NZhou, J, Neale, J.H, Pomper,M.G., Kozikowski, A.P, "NAAG Peptidase Inhibitors and their Potential for Diagnosis and Therapy." Nature Review Drug Discovery 4(2005): 1015-1026.
- Template:Note NNeale, J.H., Olszewski, R.T., Gehl, L.M., Wroblewska, B., Bzdega, T., "The neurotransmitter N-acetylaspartyl-glutamate in models of pain, ALS, diabetic neuropathy, CNS injury and schizophrenia." Trends in Pharmacological Sciences 26(2005): 477-484.
- Template:Note NOlszewski, R.T., Wegorzewska, M.M., Monteiro, A.C., Krolikowski, K.A., Zhou, J., Kozikowski, A.P., Long, K., Mastropaolo, J., Deutsch, S.I. and Neale, J.H. "Phencyclidine and Dizocilpine Induced Behaviors Reduced by N-acetylaspartylglutamate Peptidase Inhibition via Metabotropic Glutamate Receptors." Biological Psychiatry e-pub in advance of publication(2007)
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