Glutaminase inhibition and the release of neurotransmitter glutamate from synaptosomes

Bradford, H. F.; Ward, H. K.; Foley, P.

doi:10.1016/0006-8993(89)91533-3

Cited by 46 publications

(20 citation statements)

References 20 publications

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“…al. (32) have demonstrated that DON or ammonia at concentrations similar to those used in this study inhibited PAG activity and synaptosomat GLU release. Our results with DON and ammonia are in excellent agreement with the findings of Bradford et.…”

Section: Discussionmentioning

confidence: 76%

Regulation of phosphate-activated glutaminase (PAG) by glutamate analogues

Dawson

Wallace

1993

Neurochem Res

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The ability of structural analogues of glutamate (GLU) to modulate phosphate activated glutaminase (PAG) was assessed in the present series of studies. A number of GLU receptor agonists and antagonists were tested for their ability to inhibit synaptosomal PAG activity. PAG activity was determined by measuring GLU formation from 0.5 mM glutamine (GLN) in the presence of 10 mM phosphate. GLU analogues at 5-10 mM were found to significantly inhibit PAG activity. It was determined that PAG inhibition occurred regardless of whether the GLU analogues were receptor agonists or antagonists, however, PAG inhibition was influenced by analogue chain length, isomeric form and substituent substitution. The glutamate uptake blockers, dihydrokainic acid and DL-threo-beta-hydroxyaspartic acid were relatively weak inhibitors of PAG (< 25% inhibition) as were the receptor agonists, ibotenic acid and (+-)cis-2,3-piperidine-dicarboxylic acid. Other GLU analogues produced inhibition of PAG in the range of 40-70%. PAG inhibition by GLU analogues did not appear to differ substantially among the brain regions evaluated (cortex, striatum and hippocampus). The endogenous amino acids, glycine, taurine and N-acetylaspartic acid, also significantly inhibited PAG activity in the 5-10 mM range. The noncompetitive NMDA antagonists, (+)MK801 and ketamine, at a concentration of 5 mM, significantly stimulated PAG activity 1.5-2 fold over control values. The activation of PAG by (+)MK801 was dose-related, stereoselective and appeared to result from a synergistic interaction with phosphate to enhance substrate (GLN) binding to PAG.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Discussionmentioning

confidence: 76%

Regulation of phosphate-activated glutaminase (PAG) by glutamate analogues

Dawson

Wallace

1993

Neurochem Res

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“…The critical role of GLS1 has been supported further by pharmacological experiments in which a near complete depletion of neuronal glutamate was observed after inhibition of glutamine synthesis (Ottersen et al, 1992). Furthermore, direct inhibition of GLS1 by the suicide inhibitor 6-diazo-5-oxo-L-norleucine decreased the release of glutamate from cerebrocortical synaptosomes (Bradford et al, 1989), glutamate immunoreactivity in neurons (Conti and Minelli, 1994;Sulzer et al, 1998), and glutamate-dependent secretion of gonadotropinreleasing hormone from hypothalamic explants (Bourguignon et al, 1995).…”

Section: Introductionmentioning

confidence: 92%

Mice Lacking Brain/Kidney Phosphate-Activated Glutaminase Have Impaired Glutamatergic Synaptic Transmission, Altered Breathing, Disorganized Goal-Directed Behavior and Die Shortly after Birth

Masson¹,

Darmon²,

Conjard³

et al. 2006

J. Neurosci.

120

130

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Neurotransmitter glutamate has been thought to derive mainly from glutamine via the action of glutaminase type 1 (GLS1). To address the importance of this pathway in glutamatergic transmission, we knocked out GLS1 in mice. The insertion of a STOP cassette by homologous recombination produced a null allele that blocked transcription, encoded no immunoreactive protein, and abolished GLS1 enzymatic activity. Null mutants were slightly smaller, were deficient in goal-directed behavior, hypoventilated, and died in the first postnatal day. No gross or microscopic defects were detected in peripheral organs or in the CNS. In cultured neurons from the null mutants, miniature EPSC amplitude and duration were normal; however, the amplitude of evoked EPSCs decayed more rapidly with sustained 10 Hz stimulation, consistent with an observed reduction in depolarization-evoked glutamate release. Because of this activitydependent impairment in glutamatergic transmission, we surmised that respiratory networks, which require temporal summation of synaptic input, would be particularly affected. We found that the amplitude of inspirations was decreased in vivo, chemosensitivity to CO 2 was severely altered, and the frequency of pacemaker activity recorded in the respiratory generator in the pre-Bötzinger complex, a glutamatergic brainstem network that can be isolated in vitro, was increased. Our results show that although alternate pathways to GLS1 glutamate synthesis support baseline glutamatergic transmission, the GLS1 pathway is essential for maintaining the function of active synapses, and thus the mutation is associated with impaired respiratory function, abnormal goal-directed behavior, and neonatal demise.

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“…It has been suggested that this depression of excitatory transmission by ammonium ions could be due to less glutamate available presynaptically for release. Glutaminase, found in neurons, produces glutamate plus ammonia from glutamine and subsequently ammonia has shown to inhibit glutaminase (Bradford et al, 1989). In addition, brain glutamate concentrations are reduced in rats with either acute (ischemic) liver failure or thioacetamide-induced liver damage (Swain et al, 1992b).…”

Section: Glutamate Release From Neuronsmentioning

confidence: 99%

“…Unrelated to ammonia, swelling-induced glutamate release was demonstrated in cortical astrocytes exposed to a hypo-osmotic medium (Kimelberg et al, 1990). Ammonia-induced astrocytic swelling has been suggested to result in glutamine accumulation in astrocytes (by glutamine synthetase), possibly because of the inhibition of glutaminase (Bradford et al, 1989). However, an increase in extracellular brain glutamate could also lead to glutamate-induced astroglial swelling (Hansson et al, 1997).…”

Section: Calcium-independent Glutamate Releasementioning

confidence: 99%

Untitled

Rose

2002

Metabolic Brain Disease

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Glutamatergic dysfunction has been suggested to play an important role in the pathogenesis of hepatic encephalopathy (HE) in acute liver failure (ALF). Increased extracellular brain glutamate concentrations have consistently been described in different experimental animal models of ALF and in patients with increased intracranial pressure due to ALF. High brain ammonia levels remain the leading candidate in the pathogenesis of HE in ALF and studies have demonstrated a correlation between ammonia and increased concentrations of extracellular brain glutamate both clinically and in experimental animal models of ALF. Inhibition of glutamate uptake or increased glutamate release from neurons and/or astrocytes could cause an increase in extracellular glutamate. This review analyses the effect of ammonia on glutamate release from (and uptake into) both neurons and astrocytes and how these pathophysiological mechanisms may be involved in the pathogenesis of HE in ALF.

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Glutaminase inhibition and the release of neurotransmitter glutamate from synaptosomes

Cited by 46 publications

References 20 publications

Regulation of phosphate-activated glutaminase (PAG) by glutamate analogues

Regulation of phosphate-activated glutaminase (PAG) by glutamate analogues

Mice Lacking Brain/Kidney Phosphate-Activated Glutaminase Have Impaired Glutamatergic Synaptic Transmission, Altered Breathing, Disorganized Goal-Directed Behavior and Die Shortly after Birth

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