DISTRIBUTION OF <i>N</i>‐ACETYL‐ASPARTIC AND <i>N</i>‐ACETYL‐ASPARTYL‐GLUTAMIC ACIDS IN NERVOUS TISSUE*

Curatolo, A; D'Arcangelo, P; Lino, A; Brancati, A.

doi:10.1111/j.1471-4159.1965.tb06771.x

Cited by 131 publications

(51 citation statements)

References 3 publications

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“…9G). This distribution is in accordance with the distribution of NAAG in the spinal cord (1,8). NAAGS-II expression appeared to be higher in the ventral part of the spinal cord, which is in accordance with the higher NAAG concentration in ventral compared with dorsal spinal cord (19).…”

Section: Esi-ms Detection Of Naag 2 In Naags-ii Expressing Cellsto Cosupporting

confidence: 74%

N-Acetylaspartylglutamate Synthetase II Synthesizes N-Acetylaspartylglutamylglutamate

Lodder-Gadaczek¹,

Becker²,

Gieselmann

et al. 2011

Journal of Biological Chemistry

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N-Acetylaspartylglutamate (NAAG) is found at high concentrations in the vertebrate nervous system. NAAG is an agonist at group II metabotropic glutamate receptors. In addition to its role as a neuropeptide, a number of functions have been proposed for NAAG, including a role as a non-excitotoxic transport form of glutamate and a molecular water pump. We recently identified a NAAG synthetase (now renamed NAAG synthetase I, NAAGS-I), encoded by the ribosomal modification protein rimK-like family member B (Rimklb) gene, as a member of the ATP-grasp protein family. We show here that a structurally related protein, encoded by the ribosomal modification protein rimK-like family member A (Rimkla) gene, is another NAAG synthetase (NAAGS-II), which in addition, synthesizes the N-acetylated tripeptide N-acetylaspartylglutamylglutamate (NAAG 2 ). In contrast, NAAG 2 synthetase activity was undetectable in cells expressing NAAGS-I. Furthermore, we demonstrate by mass spectrometry the presence of NAAG 2 in murine brain tissue and sciatic nerves. The highest concentrations of both, NAAG 2 and NAAG, were found in sciatic nerves, spinal cord, and the brain stem, in accordance with the expression level of NAAGS-II. To our knowledge the presence of NAAG 2 in the vertebrate nervous system has not been described before. The physiological role of NAAG 2 , e.g. whether it acts as a neurotransmitter, remains to be determined. N-Acetylaspartylglutamate (NAAG)3 is an abundant peptide in the vertebrate nervous system, found at high micromolar to low millimolar concentrations (1-3). A number of studies demonstrated that NAAG acts as a specific agonist at the group II metabotropic mGluR3 glutamate receptors (4 -6). Agonistic and antagonistic effects of NAAG at N-methyl-D-asparatate receptors have been described (5, 7, 8), but could not be confirmed in later studies (9). Several reports indicate a neuroprotective role of NAAG (10 -12), and in line with this, inhibitors of the NAAG hydrolyzing glutamate carboxypeptidase (GCP)-II have a significant neuroprotective effect in different model systems (13). Increasing NAAG concentrations by GCP-II inhibition appear to reduce glutamate release through activation of presynaptic mGluR3 receptors (for review, see Ref. 13).NAAG may also be involved in neuron-glia signaling (14), although its specific role is not fully understood. Theoretically, synthesis of NAAG could also be an efficient way to transfer large amounts of glutamate from neurons to the extracellular fluid, avoiding the excitotoxic effect of free glutamate (15). A possible role of NAAG as a molecular water pump has also been suggested (16).NAAG is synthesized independently of ribosome from N-acetylaspartate (NAA) and glutamate by NAAG synthetases. Although neurons are the major source of NAAG, it is also present in cultured oligodendrocytes and activated microglia (17). In the mammalian nervous system, the highest NAAG levels have been found in the brain stem, spinal cord, and peripheral nerves (1, 18 -21). NAAG is released from synaptic ...

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Section: Esi-ms Detection Of Naag 2 In Naags-ii Expressing Cellsto Cosupporting

confidence: 74%

N-Acetylaspartylglutamate Synthetase II Synthesizes N-Acetylaspartylglutamylglutamate

Lodder-Gadaczek¹,

Becker²,

Gieselmann

et al. 2011

Journal of Biological Chemistry

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“…(6,15). Previous studies have shown that Ac-Asp-Glu is found in high concentrations (e.g., 0.5 4mol/g) in the brain but not in peripheral tissues (19,20). Furthermore, Ac-Asp-Glu has an uneven distribution in the mammalian brain, with the greatest concentration in the midbrain and brainstem (16,20,21).…”

Section: Purification Of the Peptide With L-[3h]mentioning

confidence: 96%

N-acetylaspartylglutamate: an endogenous peptide with high affinity for a brain "glutamate" receptor.

Zaczek¹,

Koller²,

Cotter³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

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A brain peptide-with high affinity (420 nM) and marked specificity for brain receptor sites labeled with L-[3H]glutamate has been identified. Amino acid analysis and mass spectroscopy indicate that the peptide is N-acetylaspartylglutamate. The peptide exhibits potent convulsant properties when injected into the rat hippocampus, similar to those produced by the glutamate receptor agonist, quisqualic acid. These findings raise the question whether endogenous brain peptides enriched in acidic amino acids may serve as excitatory neurotransmitters.The acidic amino acids L-glutamate and L-aspartate have potent excitatory effects when iontophoresed onto brain neurons (1-3). A binding site for L-[3H]glutamate has been described in the mammalian brain, which, on the basis of its subcellular distribution, pharmacologic characteristics, and ontogeny, appears to represent an excitatory receptor responsive to L-glutamate (4-7). Considerable evidence suggests that L-glutamate or Laspartate, or both, may serve as excitatory neurotransmitters in the mammalian brain (1-3). However, recently reported disparities in the ability ofantagonists to block the excitatory effects of exogenously applied glutamate or aspartate, as compared to the endogenous neurotransmitter released by putative glutamatergic neurons, have raised questions about this conclusion (8,9).In this report, we demonstrate that N-acetylaspartylglutamate (Ac-Asp-Glu), an endogenous brain peptide, exhibits a high affinity and specificity for brain receptor sites labeled with L-[3H]glutamate. Intrahippocampal injection of Ac-Asp-Glu caused a prolonged seizure disorder resembling that observed after infusion of quisqualate, a selective excitatory receptor agonist; in contrast, higher doses of L-glutamate were devoid of convulsive effects. These findings raise the question whether endogenous peptides containing acidic amino acids may be involved in excitatory neurotransmission. METHODSPeptide Purification. Immediately after decapitation, whole rat brains were removed and rapidly homogenized in 20 vol of ice-cold 0.4 M perchloric acid; the homogenate was centrifuged at 10,000 X g for 10 min at 5°C. The (13) were also examined.The amino acid content of native fractions and fractions hydrolyzed in 6 M HCI at 100°C for 12 hr was determined by the precolumn derivatization technique of Hill et aL (14). In addition, the HPLC-purified compound was subjected to characterization by mass spectroscopy (MS) on a Kratos MS-50 instrument equipped with a DS-55 data system. The purified compound was derivatized by permethylation and by trimethylsilylation.Electroencephalography. After anesthesia with pentobarbital-chlorohydrate, unipolar electrodes were inserted into the cerebral cortex at the pial surface and a reference electrode was inserted into the olfactory bulb. The electrodes were affixed with dental cement. Seven days after surgery, the electrodes were connected with a Grass, 6-channel polygraph with electroencephalogram (EEG) preamplifier, and.1 ,ul of drug or purif...

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“…N-Acetylaspartate (Ac-Asp) was identified in human brain (10) and subsequently in other mammalian species (11) and is not a neuronal excitant (12,13). N-Acetylaspartylglutamate (Ac-Asp-Glu) was isolated from the horse (14) and subsequently from other mammalian species (11). Both Ac-Asp and Ac-Asp-Glu are found only in nervous tissue (15)(16)(17).…”

mentioning

confidence: 99%

N-Acetylaspartylglutamate: possible role as the neurotransmitter of the lateral olfactory tract.

Ffrench‐Mullen¹,

Koller²,

Zaczek³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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N-Acetylaspartylglutamate, an endogenous brain peptide that binds with high affinity to a subpopulation of glutamate-binding sites in rat brain, is excitatory on rat piriform cortex pyramidal cells studied in a perfused brain slice. Both the monosynaptic excitation of the pyramidal cells elicited by stimulation of the lateral olfactory tract and the response to N-acetylaspartylglutamate were blocked by DL-2-amino-4-phosphonobutyrate but not by other excitatory amino acid antagonists. Responses to glutamate and aspartate, previously considered to be candidates as the lateral olfactory tract transmitter, were unaffected by 2-amino-4-phosphonobutyrate. Three days after unilateral bulbectomy there was a significant decrease in concentrations of N-acetylaspartylglutamate as well as aspartate, N-acetylaspartate, and y-aminobutyrate in the pyriform cortex of the side from which the olfactory bulb had been removed. These results are consistent with the possibility that N-acetylaspartylglutamate is the endogenous transmitter of the lateral olfactory tract.

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DISTRIBUTION OF N‐ACETYL‐ASPARTIC AND N‐ACETYL‐ASPARTYL‐GLUTAMIC ACIDS IN NERVOUS TISSUE*

Cited by 131 publications

References 3 publications

N-Acetylaspartylglutamate Synthetase II Synthesizes N-Acetylaspartylglutamylglutamate

N-Acetylaspartylglutamate Synthetase II Synthesizes N-Acetylaspartylglutamylglutamate

N-acetylaspartylglutamate: an endogenous peptide with high affinity for a brain "glutamate" receptor.

N-Acetylaspartylglutamate: possible role as the neurotransmitter of the lateral olfactory tract.

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