Special Issue "Role and Regulation of Glutamate Metabolism"

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (31 August 2015)

Special Issue Editor

Guest Editor
Prof. Dr. Kenneth E. Miller

Department Anatomy & Cell Biology, Oklahoma State University Center for Health Sciences (OSU-CHS), 1111 W 17TH St., Tulsa, OK 74107-1898, USA
Website | E-Mail
Phone: 918-561-5817
Interests: regulation of glutamate metabolism in dorsal root ganglion neurons during peripheral inflammation

Special Issue Information

Dear Colleagues,

Glutamate is a key amino acid related to intermediary metabolism in eukaryotic cells. A number of vertebrate tissues and organ systems, however, use glutamate and related amino acids, e.g., glutamine and aspartate, for specific functions. Neurons use glutamate as an excitatory neurotransmitter and as a precursor for the inhibitory neurotransmitter, gamma-amino butyric acid (GABA). Renal tubule cells regulate ammonia levels via glutamate production. Glutamate and glutamine are important amino acids for proper skeletal muscle function. Glutamate is influential in inflammatory activity of resident and recruited macrophages. Furthermore, many malignant cell phenotypes are dependent on glutamate metabolism for sustaining cell growth.

We invite submissions of research or review manuscripts related to the role and regulation of glutamate metabolism. Areas of interest include regulation of glutamate in specific tissue types, e.g., neuronal, glial, renal, muscle, immune, lung, intestinal, and tumor cells. These areas can include transcriptional and translational regulation of glutamate-related enzymes or transporters, intracellular signal modulation of glutamate metabolism, metabolic flux or allosteric modulation of glutamate synthesis, and the functional outcome of increased or diminished glutamate production. This issue will review recent findings and showcase original research in this diverse field.

We look forward to your contributions,

Prof. Dr. Kenneth E. Miller
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 650 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.


Keywords

  • glutamate
  • glutamine
  • aspartate
  • glutaminase
  • glutamine synthetase
  • glutamate dehydrogenase
  • aspartate aminotransferase
  • PRPP amidotransferase
  • glutamate transport
  • glutamine transport

Published Papers (6 papers)

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Research

Jump to: Review

Open AccessArticle Glutaminase Increases in Rat Dorsal Root Ganglion Neurons after Unilateral Adjuvant-Induced Hind Paw Inflammation
Biomolecules 2016, 6(1), 10; doi:10.3390/biom6010010
Received: 13 November 2015 / Revised: 31 December 2015 / Accepted: 5 January 2016 / Published: 13 January 2016
Cited by 2 | PDF Full-text (2490 KB) | HTML Full-text | XML Full-text
Abstract
Glutamate is a neurotransmitter used at both the peripheral and central terminals of nociceptive primary sensory neurons, yet little is known concerning regulation of glutamate metabolism during peripheral inflammation. Glutaminase (GLS) is an enzyme of the glutamate-glutamine cycle that converts glutamine into glutamate
[...] Read more.
Glutamate is a neurotransmitter used at both the peripheral and central terminals of nociceptive primary sensory neurons, yet little is known concerning regulation of glutamate metabolism during peripheral inflammation. Glutaminase (GLS) is an enzyme of the glutamate-glutamine cycle that converts glutamine into glutamate for neurotransmission and is implicated in producing elevated levels of glutamate in central and peripheral terminals. A potential mechanism for increased levels of glutamate is an elevation in GLS expression. We assessed GLS expression after unilateral hind paw inflammation by measuring GLS immunoreactivity (ir) with quantitative image analysis of L4 dorsal root ganglion (DRG) neurons after one, two, four, and eight days of adjuvant-induced arthritis (AIA) compared to saline injected controls. No significant elevation in GLS-ir occurred in the DRG ipsilateral to the inflamed hind paw after one or two days of AIA. After four days AIA, GLS-ir was elevated significantly in all sizes of DRG neurons. After eight days AIA, GLS-ir remained elevated in small (<400 µm2), presumably nociceptive neurons. Western blot analysis of the L4 DRG at day four AIA confirmed the elevated GLS-ir. The present study indicates that GLS expression is increased in the chronic stage of inflammation and may be a target for chronic pain therapy. Full article
(This article belongs to the Special Issue Role and Regulation of Glutamate Metabolism)
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Review

Jump to: Research

Open AccessReview Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain
Biomolecules 2016, 6(2), 16; doi:10.3390/biom6020016
Received: 29 January 2016 / Revised: 10 March 2016 / Accepted: 15 March 2016 / Published: 26 March 2016
Cited by 25 | PDF Full-text (1467 KB) | HTML Full-text | XML Full-text
Abstract
Glutamate is present in the brain at an average concentration—typically 10–12 mM—far in excess of those of other amino acids. In glutamate-containing vesicles in the brain, the concentration of glutamate may even exceed 100 mM. Yet because glutamate is a major excitatory neurotransmitter,
[...] Read more.
Glutamate is present in the brain at an average concentration—typically 10–12 mM—far in excess of those of other amino acids. In glutamate-containing vesicles in the brain, the concentration of glutamate may even exceed 100 mM. Yet because glutamate is a major excitatory neurotransmitter, the concentration of this amino acid in the cerebral extracellular fluid must be kept low—typically µM. The remarkable gradient of glutamate in the different cerebral compartments: vesicles > cytosol/mitochondria > extracellular fluid attests to the extraordinary effectiveness of glutamate transporters and the strict control of enzymes of glutamate catabolism and synthesis in well-defined cellular and subcellular compartments in the brain. A major route for glutamate and ammonia removal is via the glutamine synthetase (glutamate ammonia ligase) reaction. Glutamate is also removed by conversion to the inhibitory neurotransmitter γ-aminobutyrate (GABA) via the action of glutamate decarboxylase. On the other hand, cerebral glutamate levels are maintained by the action of glutaminase and by various α-ketoglutarate-linked aminotransferases (especially aspartate aminotransferase and the mitochondrial and cytosolic forms of the branched-chain aminotransferases). Although the glutamate dehydrogenase reaction is freely reversible, owing to rapid removal of ammonia as glutamine amide, the direction of the glutamate dehydrogenase reaction in the brain in vivo is mainly toward glutamate catabolism rather than toward the net synthesis of glutamate, even under hyperammonemia conditions. During hyperammonemia, there is a large increase in cerebral glutamine content, but only small changes in the levels of glutamate and α-ketoglutarate. Thus, the channeling of glutamate toward glutamine during hyperammonemia results in the net synthesis of 5-carbon units. This increase in 5-carbon units is accomplished in part by the ammonia-induced stimulation of the anaplerotic enzyme pyruvate carboxylase. Here, we suggest that glutamate may constitute a buffer or bulwark against changes in cerebral amine and ammonia nitrogen. Although the glutamate transporters are briefly discussed, the major emphasis of the present review is on the enzymology contributing to the maintenance of glutamate levels under normal and hyperammonemic conditions. Emphasis will also be placed on the central role of glutamate in the glutamine-glutamate and glutamine-GABA neurotransmitter cycles between neurons and astrocytes. Finally, we provide a brief and selective discussion of neuropathology associated with altered cerebral glutamate levels. Full article
(This article belongs to the Special Issue Role and Regulation of Glutamate Metabolism)
Figures

Open AccessReview On the Role of Glutamate in Presynaptic Development: Possible Contributions of Presynaptic NMDA Receptors
Biomolecules 2015, 5(4), 3448-3466; doi:10.3390/biom5043448
Received: 28 May 2015 / Revised: 22 October 2015 / Accepted: 26 November 2015 / Published: 14 December 2015
Cited by 5 | PDF Full-text (839 KB) | HTML Full-text | XML Full-text
Abstract
Proper formation and maturation of synapses during development is a crucial step in building the functional neural circuits that underlie perception and behavior. It is well established that experience modifies circuit development. Therefore, understanding how synapse formation is controlled by synaptic activity is
[...] Read more.
Proper formation and maturation of synapses during development is a crucial step in building the functional neural circuits that underlie perception and behavior. It is well established that experience modifies circuit development. Therefore, understanding how synapse formation is controlled by synaptic activity is a key question in neuroscience. In this review, we focus on the regulation of excitatory presynaptic terminal development by glutamate, the predominant excitatory neurotransmitter in the brain. We discuss the evidence that NMDA receptor activation mediates these effects of glutamate and present the hypothesis that local activation of presynaptic NMDA receptors (preNMDARs) contributes to glutamate-dependent control of presynaptic development. Abnormal glutamate signaling and aberrant synapse development are both thought to contribute to the pathogenesis of a variety of neurodevelopmental disorders, including autism spectrum disorders, intellectual disability, epilepsy, anxiety, depression, and schizophrenia. Therefore, understanding how glutamate signaling and synapse development are linked is important for understanding the etiology of these diseases. Full article
(This article belongs to the Special Issue Role and Regulation of Glutamate Metabolism)
Open AccessReview VGLUTs and Glutamate Synthesis—Focus on DRG Neurons and Pain
Biomolecules 2015, 5(4), 3416-3437; doi:10.3390/biom5043416
Received: 15 August 2015 / Revised: 13 November 2015 / Accepted: 17 November 2015 / Published: 2 December 2015
Cited by 5 | PDF Full-text (2700 KB) | HTML Full-text | XML Full-text
Abstract
The amino acid glutamate is the principal excitatory transmitter in the nervous system, including in sensory neurons that convey pain sensation from the periphery to the brain. It is now well established that a family of membrane proteins, termed vesicular glutamate transporters (VGLUTs),
[...] Read more.
The amino acid glutamate is the principal excitatory transmitter in the nervous system, including in sensory neurons that convey pain sensation from the periphery to the brain. It is now well established that a family of membrane proteins, termed vesicular glutamate transporters (VGLUTs), serve a critical function in these neurons: they incorporate glutamate into synaptic vesicles. VGLUTs have a central role both under normal neurotransmission and pathological conditions, such as neuropathic or inflammatory pain. In the present short review, we will address VGLUTs in the context of primary afferent neurons. We will focus on the role of VGLUTs in pain triggered by noxious stimuli, peripheral nerve injury, and tissue inflammation, as mostly explored in transgenic mice. The possible interplay between glutamate biosynthesis and VGLUT-dependent packaging in synaptic vesicles, and its potential impact in various pain states will be presented. Full article
(This article belongs to the Special Issue Role and Regulation of Glutamate Metabolism)
Open AccessReview Overview of Glutamatergic Dysregulation in Central Pathologies
Biomolecules 2015, 5(4), 3112-3141; doi:10.3390/biom5043112
Received: 5 October 2015 / Revised: 3 November 2015 / Accepted: 5 November 2015 / Published: 11 November 2015
Cited by 16 | PDF Full-text (989 KB) | HTML Full-text | XML Full-text
Abstract
As the major excitatory neurotransmitter in the mammalian central nervous system, glutamate plays a key role in many central pathologies, including gliomas, psychiatric, neurodevelopmental, and neurodegenerative disorders. Post-mortem and serological studies have implicated glutamatergic dysregulation in these pathologies, and pharmacological modulation of glutamate
[...] Read more.
As the major excitatory neurotransmitter in the mammalian central nervous system, glutamate plays a key role in many central pathologies, including gliomas, psychiatric, neurodevelopmental, and neurodegenerative disorders. Post-mortem and serological studies have implicated glutamatergic dysregulation in these pathologies, and pharmacological modulation of glutamate receptors and transporters has provided further validation for the involvement of glutamate. Furthermore, efforts from genetic, in vitro, and animal studies are actively elucidating the specific glutamatergic mechanisms that contribute to the aetiology of central pathologies. However, details regarding specific mechanisms remain sparse and progress in effectively modulating glutamate to alleviate symptoms or inhibit disease states has been relatively slow. In this report, we review what is currently known about glutamate signalling in central pathologies. We also discuss glutamate’s mediating role in comorbidities, specifically cancer-induced bone pain and depression. Full article
(This article belongs to the Special Issue Role and Regulation of Glutamate Metabolism)
Open AccessReview Computational Studies of Glutamate Transporters
Biomolecules 2015, 5(4), 3067-3086; doi:10.3390/biom5043067
Received: 25 September 2015 / Revised: 29 October 2015 / Accepted: 3 November 2015 / Published: 11 November 2015
Cited by 2 | PDF Full-text (1293 KB) | HTML Full-text | XML Full-text
Abstract
Glutamate is the major excitatory neurotransmitter in the human brain whose binding to receptors on neurons excites them while excess glutamate are removed from synapses via transporter proteins. Determination of the crystal structures of bacterial aspartate transporters has paved the way for computational
[...] Read more.
Glutamate is the major excitatory neurotransmitter in the human brain whose binding to receptors on neurons excites them while excess glutamate are removed from synapses via transporter proteins. Determination of the crystal structures of bacterial aspartate transporters has paved the way for computational investigation of their function and dynamics at the molecular level. Here, we review molecular dynamics and free energy calculation methods used in these computational studies and discuss the recent applications to glutamate transporters. The focus of the review is on the insights gained on the transport mechanism through computational methods, which otherwise is not directly accessible by experimental probes. Recent efforts to model the mammalian glutamate and other amino acid transporters, whose crystal structures have not been solved yet, are included in the review. Full article
(This article belongs to the Special Issue Role and Regulation of Glutamate Metabolism)

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Type of Paper: Review
Title:
Computational Studies of Glutamate Transporters and Receptors
Authors: Serdar Kuyucak
Affiliation:
School of Physics, University of Sydney, Sydney, New South Wales 2006, Australia;
E-Mail: serdar@physics.usyd.edu.au
Abstract:
Glutamate is the major excitatory neurotransmitter in the human brain whose binding to receptors on neurons excites them while excess glutamate are removed from synapses via transporter proteins. Determination of the crystal structures of glutamate transporters and receptors has paved the way for computational investigation of their function at the molecular level. Here we review the molecular dynamics and free energy simulation methods used in these computational studies, and discuss the recent applications to glutamate transporters and receptors. The focus of the review is on the insights gained on the transport mechanism through computational methods, which otherwise is not directly accessible by experimental probes. Recent efforts to model the mammalian glutamate transporters, whose crystal structures have not been solved yet, are included in the review.

Type of Paper: Review
Title:
Central Role of Glutamate Metabolism in the Maintenance of Nitrogen Homeostasis in Normal and Hyperammonemic Brain
Authors:
Arthur J. L. Cooper and Thomas M. Jeitner
Affiliation:
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA;
E-Mail: arthur_cooper@nymc.edu (A.J.L.C.); Thomas_Jeitner@nymc.edu (T.M.J.)
Abstract
: Glutamate is present in the brain at an average concentration (typically 10-12 mM), far in excess of those of other amino acids. In glutamate-containing vesicles in the brain the concentration of glutamate may even exceed 100 mM. Yet because glutamate is a major excitatory neurotransmitter the concentration of this amino acid in the cerebral extracellular fluid must be kept low – typically µM. The remarkable gradient of glutamate in the different cerebral compartments (i.e., vesicles > cytosol/mitochondria > extracellular fluid) attests to the extraordinary effectiveness of glutamate transporters and the strict control of enzymes of glutamate synthesis and catabolism in well-defined cellular and subcellular compartments in the brain. Although the glutamate transporters are briefly discussed the major emphasis of the present review is on the enzymology contributing to the maintenance of glutamate levels under normal and hyperammonemic conditions. A major route for glutamate and ammonia removal is via the glutamine synthetase reaction. Glutamate is also removed by conversion to the inhibitory neurotransmitter GABA via the action of glutamate decarboxylase. On the other hand, cerebral glutamate levels are maintained by the action of glutaminase and by various α-ketoglutarate-linked aminotransferases (particularly aspartate aminotransferase and the mitochondrial and cytosolic forms of the branched-chain aminotransferases). Although the glutamate dehydrogenase reaction is freely reversible, owing to rapid removal of ammonia as glutamine, the direction of the glutamate dehydrogenase reaction in the brain in vivo is toward glutamate catabolism rather than toward the net synthesis of glutamate, even under hyperammonemia conditions. During hyperammonemia there is a large increase in cerebral glutamine content, but only small changes in the level of glutamate and α-ketoglutarate. In other words, hyperammonemia stimulates the net synthesis of 5-C units. This is accomplished by the ammonia-induced stimulation of the anaplerotic enzyme pyruvate carboxylase. Emphasis in this review will be on the central role of glutamate in the glutamate-glutamine and GABA-glutamine neurotransmitter cycles between neurons and astrocytes. Also discussed will be the recent finding of a “new” glutamate dehydrogenase isozyme in human brain and its possible relationship to neurodegenerative diseases.

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