Electrophysiological and pharmacological actions of N-acetylaspartylglutamate intracellularly studied in cultured chick cerebellar neurons

Mori-Okamoto, Junko; Okamoto, Koichi; Sekiguchi, Masayuki

doi:10.1016/0006-8993(87)91164-4

Cited by 40 publications

(15 citation statements)

References 18 publications

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“…Oocytes injected with NMDAR1 receptor subunit cDNA formed homomeric receptors that were activated by the peptide, whereas cells injected with AMPA and kainate receptor cDNAs were not (Sekiguchi et al, 1992). NAAG also activated NMDA‐like receptors on guinea pig and chick cerebellar neurons (Mori‐Okamoto et al, 1987 ; Sekiguchi et al, 1987) and elicited increases in intracellular calcium in neurons cultured from rat forebrain via NMDA‐like receptors (Koenig et al, 1994).…”

Section: Nmda Receptors and Naagmentioning

confidence: 99%

N‐Acetylaspartylglutamate

Neale

Bzdega

Wróblewska

2000

Journal of Neurochemistry

317

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In the progress of science, as in life, timing is important. The acidic dipeptide, N-acetylaspartylglutamate (NAAG), was discovered in the mammalian nervous system in 1965, but initially was not considered to be a neurotransmitter candidate. In the mid-1980s, a few laboratories revisited the question of NAAG's role in the nervous system and pursued hypotheses regarding its function that ranged from a precursor for the transmitter pool of glutamate to a direct role as a peptide transmitter. Since that time, NAAG has been tested against nearly all of the established criteria for identification of a neurotransmitter. It successfully meets each of these tests, including a concentrated presence in neurons and synaptic vesicles, release from axon endings in a calcium-dependent manner following initiation of action potentials, and extracellular hydrolysis by membrane-bound peptidase activity. NAAG is the most prevalent and widely distributed neuropeptide in the mammalian nervous system. NAAG activates NMDA receptors with a low potency that may vary among receptor subtypes, and it is a highly selective agonist at the type 3 metabotropic glutamate receptor (mGluR3). Acting through this receptor, NAAG reduces cyclic AMP levels, decreases voltage-dependent calcium conductance, suppresses excitotoxicity, influences long-term potentiation and depression, regulates GABA(A) receptor subunit expression, and inhibits synaptic release of GABA from cortical neurons. Cloning of peptidase activities against NAAG provides opportunities to study the cellular and molecular mechanisms by which synaptic NAAG peptidase activity is controlled. Given the codistribution of this peptide with a spectrum of traditional transmitters and its ability to activate mGluR3, we speculate that one role for NAAG following synaptic release is the activation of metabotropic autoreceptors that inhibit subsequent transmitter release. A second role is the production of extracellular glutamate following NAAG hydrolysis.

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Section: Nmda Receptors and Naagmentioning

confidence: 99%

N‐Acetylaspartylglutamate

Neale

Bzdega

Wróblewska

2000

Journal of Neurochemistry

317

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“…An initial study suggesting a direct excitatory synaptic action for NAAG in the lateral olfactory tract (ffrench-Mullen et al, 1985) seems likely to have been confounded by the presence of elevated levels of potassium in the peptide preparation (Whittemore and Koerner, 1989). Beyond this, there is little agreement as to the excitatory potency of the peptide in several systems that respond to acidic amino acid agonists and that contain substantial amounts of endogenous NAAG (Luini et al, 1984;Bernstein et al, 1985;Westbrook et al, 1986;Mori-Okamoto et al, 1987;Sekiguchi et al, 1987;Henderson and Salt, 1988;Schneider and Perl, 1988). Equilibrium binding studies, which purported to demonstrate affinity between the peptide and an acidic amino acid receptor subtype (Koller and Coyle, 1985;Schoepp and Johnson, 1989), were not definitive inasmuch as they failed to account for the influence of the binding of glutamate released via peptidase activity (Riveros and Orrego, 1984;Blakely ef al., 1988).…”

Section: Introductionmentioning

confidence: 99%

Localization and Synaptic Release of N‐acetylaspartyl‐glutamate in the Chick Retina and Optic Tectum

Williamson

Eagles

Brady

et al. 1991

Eur J of Neuroscience

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The neuropeptide, N-acetylaspartylglutamate (NAAG), was identified in the chick retina (1.4 nmol/retina) by HPLC, radioimmunoassay and immunohistochemistry. This acidic dipeptide was found within retinal ganglion cell bodies and their neurites in the optic fibre layer of the retina. Substantial, but less intense, immunoreactivity was detected in many amacrine-like cells in the inner nuclear layer and in multiple bands within the inner plexiform layer. In addition, NAAG immunoreactivity was observed in the optic fibre layer and in the neuropil of the superficial layers of the optic tectum, as well as in many cell bodies in the tectum. Using a newly developed, specific and highly sensitive (3 fmol/50 microl) radioimmunoassay for NAAG, peptide release was detected in isolated retinas upon depolarization with 55 mM extracellular potassium. This assay also permitted detection of peptide release from the optic tectum following stimulation of action potentials in retinal ganglion cell axons of the optic tract. Both of these release processes required the presence of extracellular calcium. Electrically stimulated release from the tectum was reversibly blocked by extracellular cadmium. These findings suggest that NAAG serves an extracellular function following depolarization-induced release from retinal amacrine neurons and from ganglion cell axon endings in the chick optic tectum. These data support the hypothesis that NAAG functions in synaptic communication between neurons in the visual system.

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“…It is concentrated in neurons (Anderson et al, 1986;Forloni et al, 1987;Tie-man et al, 1991), is associated with synaptic vesicles (Williamson and Neale, 1988a), is released in a calcium-dependent manner after depolarization of neurons (Pittaluga et al, 1988;Tsai et al, 1988;Williamson and Neale, 1988b;Zollinger et al, 1988;Williamson et al, 199 I), and is hydrolyzed by an extracellular peptidase (Riveros and Orrego, 1984;Blakely et al, 1986;Robinson et al, 1987;Serval et al, 1990Serval et al, , 1992Williamson and Neale, 1992). Responses to the application of NAAG have vaned between cell systems (Bernstein et al, 1985;Joels et al, 1987;Mori-Oka-mot0 et al, 1987;Sekiguchi et al, 1987Sekiguchi et al, , 1989Henderson and Salt, 1988;Galli et al, 199 1). With respect to characterization of its actions at specific receptors, the peptide has been demonstrated to act as a low potency agonist at N-methyl-D-aspartate (NMDA) receptors on spinal cord neurons (Westbrook et al, 1986) and olfactory mitral cells (Trombley and Westbrook, 1990).…”

mentioning

confidence: 99%

N‐Acetylaspartylglutamate Inhibits Forskolin‐Stimulated Cyclic AMP Levels via a Metabotropic Glutamate Receptor in Cultured Cerebellar Granule Cells

Wróblewska

Wroblewski

Saab

et al. 1993

Journal of Neurochemistry

109

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The neuronal dipeptide N-acetylaspartylglutamate (NAAG) fulfills several of the criteria for classification as a neurotransmitter including localization in synaptic vesicles, calcium-dependent release after neuronal depolarization, and low potency activation of N-methyl-D-aspartate receptors. In the present study, the influence of NAAG on metabotropic receptor activation in cerebellar granule cells was examined in cell culture. Stimulation of granule cell adenylate cyclase with forskolin increased cyclic AMP (cAMP) several hundredfold above basal levels within 10 min in a concentration-dependent manner. Although glutamate, NAAG, and the metabotropic receptor agonist trans-1-amino-1,3-cyclopentanedicarboxylic acid did not alter the low basal cAMP levels, the application of 300 microM glutamate or NAAG or trans-1-amino-1,3-cyclopentanedicarboxylic acid reduced forskolin-stimulated cAMP in granule cells by 30-50% in the absence or presence of inhibitors of ionotropic acidic amino acid receptors, as well as 2-amino-4-phosphonobutyrate. No additivity in the inhibition of cAMP was found when 300 microM NAAG and trans-1-amino-1,3-cyclopentanedicarboxylic acid were coapplied. The beta-analogue of NAAG failed to reduce cAMP levels. Similar effects of NAAG and glutamate were obtained under conditions of inhibition of phosphodiesterase activity and were prevented by pretreatment of the cells with pertussis toxin. These data are consistent with the activation by NAAG of a metabotropic acidic amino acid receptor coupled to an inhibitory G protein. In contrast, the metabotropic acidic amino acid receptor coupled to phosphoinositol turnover in these cells was not activated by NAAG.(ABSTRACT TRUNCATED AT 250 WORDS)

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Electrophysiological and pharmacological actions of N-acetylaspartylglutamate intracellularly studied in cultured chick cerebellar neurons

Cited by 40 publications

References 18 publications

N‐Acetylaspartylglutamate

N‐Acetylaspartylglutamate

Localization and Synaptic Release of N‐acetylaspartyl‐glutamate in the Chick Retina and Optic Tectum

N‐Acetylaspartylglutamate Inhibits Forskolin‐Stimulated Cyclic AMP Levels via a Metabotropic Glutamate Receptor in Cultured Cerebellar Granule Cells

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