Glutamine Synthetase: The Major Mn(II) Enzyme in Mammalian Brain

Wedler, Frederick C.; Denman, Robert B.

doi:10.1016/b978-0-12-152824-9.50021-6

Cited by 182 publications

(112 citation statements)

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“…Moreover, Mn plays a role in the modulation of the immune system, and in protein, lipid and carbohydrate metabolism (Addess et al, 1997;Aschner et al, 1992;Fitsanakis et al, 2005;Malecki et al, 1999). Evidence also corroborates the involvement of Mn in the stellate process production in astrocytes (Liao et al, 2001), as well as in the metabolism of brain glutamate to glutamine, a step carried out by the astrocyte-specific enzyme, glutamine synthetase (Wedler et al, 1982;Wedler et al, 1984;Takeda, 2003).Despite its essentiality in multiple metabolic functions, Mn can be toxic at high concentrations. The brain, in particular, is highly susceptible to Mn toxicity.…”

supporting

confidence: 54%

“…Mn deficiency may result in birth defects, poor bone formation and an increased susceptibility to seizures (Aschner, 2000;Aschner et al, 2002). As an essential metal, it is a co-factor for many enzymes such as transferases, hydrolases, lyases, glutamine synthetase and integrins (Saric, 1986;Wedler et al, 1984). The most well studied Mn-containing polypeptides are arginase, an enzyme present in lipids that is required for ammonia elimination, and Mncontaining superoxide dismutase (Mn-SOD), a principal anti-oxidant enzyme typically found in the mitochondria.…”

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confidence: 99%

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Manganese transport in eukaryotes: The role of DMT1

2008

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Manganese (Mn) is a transition metal that is essential for normal cell growth and development, but is toxic at high concentrations. While Mn deficiency is uncommon in humans, Mn toxicity is known to be readily prevalent due to occupational overexposure in miners, smelters and possibly welders. Excessive exposure to Mn can cause Parkinson's disease-like syndrome; patients typically exhibit extrapyramidal symptoms that include tremor, rigidity and hypokinesia (Calne et al., 1994;Dobson et al., 2004).Mn-induced motor neuron diseases have been the subjects of numerous studies; however, this review is not intended to discuss its neurotoxic potential or its role in the etiology of motor neuron disorders. Rather, it will focus on Mn uptake and transport via the orthologues of the divalent metal transporter (DMT1) and its possible implications to Mn toxicity in various categories of eukaryotic systems, such as in vitro cell lines, in vivo rodents, the fruitfly, Drosophila melanogaster, the honeybee, Apis mellifera L., the nematode, Caenorhabditis elegans, and the baker's yeast, Saccharomyces cerevisiae. Keywords DMT1; Manganese; NRAMP-2; Transport ManganeseMn is one of the most abundant naturally occurring elements in the earth's crust; it does not occur naturally in a pure state. Oxides, carbonates and silicates are the most important Mncontaining minerals (Post, 1999). Depending on its oxidation state, Mn is utilized in countless industrial processes, such as the production of dry cell batteries, steel (Post, 1999; Saric, 1986), fuel oil additives and antiknock agents (Pfeifer et al., 2004;Ressler et al., 1999;Rollin et al., 2005). *Corresponding Author: Michael Aschner, PhD, 2215-B Garland Avenue, 11425 MRB IV, Vanderbilt University Medical Center, Nashville, michael.aschner@vanderbilt.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeurotoxicology. Author manuscript; available in PMC 2009 July 1. Published in final edited form as:Neurotoxicology. 2008 July ; 29(4): 569-576. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe major source of Mn in humans is through dietary ingestion. Approximately 3-5% of ingested Mn is absorbed across the intestinal wall, and the remainder is excreted in feces, representing tight homeostatic control over Mn absorption. Mn toxicity from dietary intake is rare; its uptake is tightly regulated, and any excess of ingested Mn is readily excreted via the bile. In contrast, both pulmonary uptake and particulate transport via the olfactory bulb (Saric, 1986;Aschner et al., 1991...

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confidence: 99%

Manganese transport in eukaryotes: The role of DMT1

2008

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“…As an essential element, Mn plays a vital role for normal development and body functions across the life span of all mammals (Keen et al, 2000). In brain about 80% of Mn is associated with the astrocyte specific enzyme glutamine synthase (Wedler and Denman, 1984). Excessive levels of brain Mn has *To Whom the Correspondence Should be Addressed: Dr. Wei Zheng, Ph.D., Purdue University School of Health Sciences, 550 Stadium Mall Drive, CIVL 1163D, West Lafayette, IN 47907, Phone: 765-496-6447, Fax: 765-496-1377, E-mail: wzheng@purdue.edu.…”

Section: Introductionmentioning

confidence: 99%

Manganese accumulates primarily in nuclei of cultured brain cells

2008

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Manganese (Mn) is known to pass across the blood-brain barrier and interact with dopaminergic neurons. However, the knowledge on the subcellular distribution of Mn in these cell types upon exposure to Mn remained incomplete. This study was designed to investigate the subcellular distribution of Mn in blood-brain barrier endothelial RBE4 cells, blood-cerebrospinal fluid barrier choroidal epithelial Z310 cells, mesencephalic dopaminergic neuronal N27 cells, and pheochromocytoma dopaminergic PC12 cells. The cells were incubated with 100 µM MnCl 2 with radioactive tracer 54 Mn in the culture media for 24 hrs. The subcellular organelles, i.e., nuclei, mitochondria, microsomes, and cytoplasm, were isolated by centrifugation and verified for their authenticity by determining the markers specific to cellular organelles. Data indicated that maximum Mn accumulation was observed in PC12 cells, which was 2.8, 5.2 and 5.9 fold higher than that in N27, Z310 and RBE4 cells, respectively. Within cells, about 92%, 72%, and 52% of intracellular 54 Mn were found to be present in nuclei of RBE4, Z310, and N27 cells, respectively. The recovery of 54 Mn in nuclei and cytoplasm of PC12 cells were 27% and 69% respectively. Surprisingly, less than 0.5% and 2.5% of cellular 54 Mn was found in mitochondrial and microsomal fractions, respectively. This study suggests that the nuclei may serve as the primary pool for intracellular Mn; mitochondria and microsomes may play an insignificant role in Mn subcellular distribution.

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“…Once the Mn 2þ has reached the brain interstitial fluid by the route outlined above or by other routes that circumvent the BBB, the distribution across the different cell types in the brain is such that glial cells, particularly astrocytes, seem to play a role as a ''sink'' for brain Mn 2þ (74), with concentrations 10-50-fold greater than those found in neurons. As astrocytes maintain brain homoeostasis through precise regulation of extracellular constituents, they efficiently transport Mn 2þ , and an astrocyte-specific manganoprotein critical for ammonia metabolism, glutamine synthetase, accounts for about 80% of the total brain Mn 2þ (74).…”

Section: Molecular Mechanisms Of Memrimentioning

confidence: 99%

“…As astrocytes maintain brain homoeostasis through precise regulation of extracellular constituents, they efficiently transport Mn 2þ , and an astrocyte-specific manganoprotein critical for ammonia metabolism, glutamine synthetase, accounts for about 80% of the total brain Mn 2þ (74). The precise transporter(s) for Mn 2þ into astrocytes is unknown; however, it has been suggested that transferrin receptor and/or bivalent metal transporter proteins may be important.…”

Section: Molecular Mechanisms Of Memrimentioning

confidence: 99%

Current status of functional MRI on small animals: application to physiology, pathophysiology, and cognition

et al. 2007

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This review aims to make the reader aware of the potential of functional MRI (fMRI) in brain activation studies in small animal models. As small animals generally require anaesthesia for immobilization during MRI protocols, this is believed to be a serious limitation to the type of question that can be addressed with fMRI. We intend to introduce a fresh view with an in-depth overview of the surprising number of fMRI applications in a wide range of important research domains in neuroscience. These include the pathophysiology of brain functioning, the basic science of activity, and functional connectivity of different sensory circuits, including sensory brain mapping, the challenges when studying the hypothalamus as the major control centre in the central nervous system, and the limbic system as neural substrate for emotions and reward. Finally the contribution of small animal fMRI research to cognitive neuroscience is outlined. This review avoids focusing exclusively on traditional small laboratory animals such as rodents, but rather aims to broaden the scope by introducing alternative lissencephalic animal models such as songbirds and fish, as these are not yet well recognized as neuroimaging study subjects. These models are well established in many other neuroscience disciplines, and this review will show that their investigation with in vivo imaging tools will open new doors to cognitive neuroscience and the study of the autonomous nervous system in experimental animals.

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Glutamine Synthetase: The Major Mn(II) Enzyme in Mammalian Brain

Cited by 182 publications

References 0 publications

Manganese transport in eukaryotes: The role of DMT1

Manganese transport in eukaryotes: The role of DMT1

Manganese accumulates primarily in nuclei of cultured brain cells

Current status of functional MRI on small animals: application to physiology, pathophysiology, and cognition

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