Synthesis and release of N-acetylaspartylglutamate (NAAG) by crayfish nerve fibers: implications for axon–glia signaling

Urazaev, A. Kh.; Grossfeld, Robert M.; Fletcher, Paul L.; Speno, Henry; Gafurov, Boris; Buttram, J.G; Lieberman, Edward M.

doi:10.1016/s0306-4522(01)00270-6

Cited by 34 publications

(33 citation statements)

References 47 publications

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“…The presence of a "NAAG synthetase" enzyme has been postulated based on indirect means in several studies (Arun et al, 2006;Cangro et al, 1987;Gehl et al, 2004;Urazaev et al, 2001;Williamson and Neale, 1988). Most recent studies which have successfully demonstrated NAAG biosynthesis were done in neural explants, including excised rat dorsal root ganglia (Cangro et al, 1987), excised frog retinas (Williamson and Neale, 1988), crayfish nerve cord (Urazaev et al, 2001) and hemisected rat spinal cord (Gehl et al, 2004). In several recent reports, NAAG biosynthesis has been observed in cell culture, including primary rat astrocyte cell culture (Gehl et al, 2004), and in a continuous human neuroblastoma cell line (Arun et al, 2004;Arun et al, 2006).…”

Section: Evidence For a Naag Synthetase Enzymementioning

confidence: 99%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,230

1,126

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The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.

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Section: Evidence For a Naag Synthetase Enzymementioning

confidence: 99%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,230

1,126

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“…Glutamate release from astrocytes may involve membrane channels or transporters or extracellular synthesis from secreted precursors such as N-acetylaspartylglutamate (35). Also, substances other than glutamate and ATP, for example, the inhibitory neurotransmitter γ-aminobutyric acid (GABA) (36 ), peptides (37 ), or growth factors (38), may participate in neuron-glial signaling.…”

Section: Glial Regulation Of Synaptic Strengthmentioning

confidence: 99%

New Insights into Neuron-Glia Communication

Fields

Stevens-Graham

2002

Science

850

522

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Two-way communication between neurons and nonneural cells called glia is essential for axonal conduction, synaptic transmission, and information processing and thus is required for normal functioning of the nervous system during development and throughout adult life. The signals between neurons and glia include ion fluxes, neurotransmitters, cell adhesion molecules, and specialized signaling molecules released from synaptic and nonsynaptic regions of the neuron. In contrast to the serial flow of information along chains of neurons, glia communicate with other glial cells through intracellular waves of calcium and via intercellular diffusion of chemical messengers. By releasing neurotransmitters and other extracellular signaling molecules, glia can affect neuronal excitability and synaptic transmission and perhaps coordinate activity across networks of neurons.Historically, neuroscientists suspected that nonneural cells called glial cells might contribute to information processing in the brain. However, the supporting evidence was comparatively meager because glia have been studied with tools used to probe the electrical excitability of neurons. Although many of the same voltage-sensitive ion channels and neurotransmitter receptors of neurons are found in glia (1), glial cells lack the membrane properties required to fire action potentials. Nevertheless, these ion channels and electrogenic membrane transporters allow glia to sense indirectly the level of neuronal activity by monitoring activity-dependent changes in the chemical environment shared by these two cell types. Advanced imaging methods, which allow observation of changes in intracellular and extracellular signaling molecules in real time, show that glia communicate with one another and with neurons primarily through chemical signals rather than electrical signals (see Movie S1). Many of these signaling systems overlap with the neurotransmitter signaling systems of neurons, but some are specialized for glial-glial and neuron-glial communication.This expanded relationship between neurons and glia is challenging traditional neurobiology. Contrary to dogma, some neurons in the central nervous system (CNS) use rapid neurotransmission not only at synapses with other neurons, but also at synapses with glia as well. Furthermore, neural activity releases chemical messengers not only at synaptic junctions, but also in extrasynaptic regions of neurons. This suggests functions for neuron-glial communication beyond those associated with synaptic transmission. For example, glia can regulate synapse formation, can control synaptic strength, and may participate in information processing by coordinating activity among sets of neurons. Conversely, neural impulse activity regulates a wide range of glial activities, including their proliferation, differentiation, and myelination.

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“…More importantly, decreased glutamate availability from NAAG by inhibition of GCP II could decrease the excitability of the neuroma at the injured nerve. GCP II is located extensively in Schwann cells of the peripheral nerve and may be involved in the signaling between axons and Schwann cells during nerve degeneration or regeneration following nerve injury (Berger et al, 1995;Urazaev et al, 2001). At this time, little is known about GCP II, NAAG, and glutamate metabolism at the site of nerve injury.…”

Section: Gcp II Inhibitor and Neuropathic Pain 665mentioning

confidence: 99%

Effect of 2-(Phosphono-methyl)-pentanedioic Acid on Allodynia and Afferent Ectopic Discharges in a Rat Model of Neuropathic Pain

Chen¹,

Wozniak²,

Slusher³

et al. 2002

J Pharmacol Exp Ther

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Increased glutamate availability in the spinal cord and primary afferent nerves plays an important role in acute and chronic pain. Afferent ectopic discharges from the site of nerve injury constitute a source of abnormal sensory input to the spinal dorsal horn. The ectopic afferent activity is largely responsible for the development of hypersensitivity of dorsal horn neurons and neuropathic pain. Inhibition of glutamate carboxypeptidase II (GCP II) reduces glutamate release generated from N-acetylaspartyl-glutamate in nerve tissues and may have an analgesic effect on neuropathic pain. In the present study, we determined the effect of a GCP II inhibitor, 2-(phosphono-methyl)-pentanedioic acid (2-PMPA), on allodynia and ectopic afferent discharges in an animal model of neuropathic pain. Neuropathic pain was induced by partial ligation of the left sciatic nerve in

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Synthesis and release of N-acetylaspartylglutamate (NAAG) by crayfish nerve fibers: implications for axon–glia signaling

Cited by 34 publications

References 47 publications

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

New Insights into Neuron-Glia Communication

Effect of 2-(Phosphono-methyl)-pentanedioic Acid on Allodynia and Afferent Ectopic Discharges in a Rat Model of Neuropathic Pain

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