N-Acetylaspartylglutamate
Encyclopedia
N-Acetylaspartylglutamic acid (N-acetylaspartylglutamate or NAAG) is a neuropeptide that is the third-most-prevalent neurotransmitter
in the mammalian nervous system. NAAG consists of N-acetylaspartic acid (NAA) and glutamic acid
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. It meets the criteria for a neurotransmitter
, including being concentrated in neuron
s, 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.
s in a manner relevant to physiology is controversial, its primary receptor was long believed to be 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. Stimulation of the mGluR3 by NAAG has been, however, questioned, finding relevant glutamate contamination in commercially available NAAG.
According to one publication, NAAG can be differentiated from NAA in vivo
by MR spectroscopy at 3 Tesla.
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 finding suggests that PKA and PKC have opposing regulatory effects on the NAAG synthetase enzyme.
-based analogs of NAAG, including ZJ43, ZJ17, and ZJ11. 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 release of transmitter (glutamate) 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 co-therapy for schizophernia. In these cases, NAAG peptidase inhibition reduces the adverse effects in these disorders. Future research focuses on 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.
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
in the mammalian nervous system. NAAG consists of N-acetylaspartic acid (NAA) and glutamic acid
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
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. It meets the criteria for a neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
, including being concentrated in neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s, 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
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
spaglumic acid, NAAG is used as an antiallergic
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
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. Second, it did not seem to directly affect membrane potential, so it was classified as a metabolic intermediate. The importance of brain peptides became clearer with the discovery of endogenous opioids. Whereas the ability of NAAG to interact with NMDA receptorNMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s in a manner relevant to physiology is controversial, its primary receptor was long believed to be the mGluR3
Metabotropic glutamate receptor 3
Metabotropic glutamate receptor 3 is a protein that in humans is encoded by the GRM3 gene.-Ligands:Though truly mGluR3 selective agents still await their discovery, mixed mGluR2/3 ligands with selectivity over other mGluR-subtypes are known...
. Its interaction with the mGluR3 causes an activation of G proteins that reduce the concentration of the second messengers cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
and cGMP
Cyclic guanosine monophosphate
Cyclic guanosine monophosphate is a cyclic nucleotide derived from guanosine triphosphate . cGMP acts as a second messenger much like cyclic AMP...
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. Stimulation of the mGluR3 by NAAG has been, however, questioned, finding relevant glutamate contamination in commercially available NAAG.
According to one publication, NAAG can be differentiated from NAA in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
by MR spectroscopy at 3 Tesla.
Biosynthesis
NAAG synthetase activity mediates the biosynthesis of NAAG from glutamate and NAA, but little is known about the mechanism or regulation of this enzyme, and no NAAG synthetase activity has been isolated in cell-free preparations. 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 neuroblastomaNeuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
cells, it has been shown that a protein kinase A (PKA) activator will increase the quantity of NAAG, while a protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
(PKC) activator will decrease its concentration. This finding suggests that PKA and PKC have opposing regulatory effects on the NAAG synthetase enzyme.
Catabolism
NAAG is catabolized via NAAG peptidase activity. Two enzymes with NAAG peptidase activity have been cloned, glutamate carboxypeptidase II and glutamate carboxypeptidase III. These enzymes mediate the hydrolysis of NAAG to NAA and glutamate. Their inhibition can produce therapeutic benefits. Two main types of inhibitors of this enzyme are known: compounds related to 2-(phosphonomethyl)pentanedioic acid (2-PMPA) and ureaUrea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
-based analogs of NAAG, including ZJ43, ZJ17, and ZJ11. 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 release of transmitter (glutamate) in the pain signaling pathways of the spinal cord and brain. In the case of traumatic brain injury
Traumatic brain injury
Traumatic brain injury , also known as intracranial injury, occurs when an external force traumatically injures the brain. TBI can be classified based on severity, mechanism , or other features...
, the injection of a NAAG peptidase inhibitor reduces neuron and astrocyte
Astrocyte
Astrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
death in the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
nearest the site of the injury. In a mouse model of amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
(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
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, animals were injected with phencyclidine
Phencyclidine
Phencyclidine , commonly initialized as PCP and known colloquially as angel dust, is a recreational dissociative drug...
(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 co-therapy for schizophernia. In these cases, NAAG peptidase inhibition reduces the adverse effects in these disorders. Future research focuses on 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.