Kinetics of a Novel Isoform of Phosphate Activated Glutaminase (PAG) in SH-SY5Y Neuroblastoma Cells

Roberg, Bjørg; Torgner, Ingeborg Aa.; Kvamme, Elling

doi:10.1007/s11064-009-0077-7

Cited by 7 publications

(3 citation statements)

References 20 publications

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“…In this respect, without glutamine influx, SH-SY5Y cells cannot produce glutamate in glutamine-free medium (40). The neuroblastoma cell line, SH-SY5Y, expresses a novel form of phosphate activated glutaminase (PAG) which deamidates glutamine to glutamate and ammonia at high rates (41). Glutamate dyshomeostasis and oxidative stress have been identified as two critical mechanisms mediating MeHg-induced neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Glutamate-mediated effects of caffeine and interferon-γ on mercury-induced toxicity

Engin

Golokhvast

et al. 2017

International Journal of Molecular Medicine

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The molecular mechanisms mediating mercury-induced neurotoxicity are not yet completely understood. Thus, the aim of this study was to investigate whether the severity of MeHg- and HgCl2-mediated cytotoxicity to SH-SY5Y human dopaminergic neurons can be attenuated by regulating glutamate-mediated signal-transmission through caffeine and interferon-γ (IFN-γ). The SH-SY5Y cells were exposed to 1, 2 and 5 μM of either MeHgCl2 or HgCl2 in the presence or absence of L-glutamine. To examine the effect of adenosine receptor antagonist, the cells were treated with 10 and 20 μM caffeine. The total mitochondrial metabolic activity and oxidative stress intensity coefficient were determined in the 1 ng/ml IFN-γ- and glutamate-stimulated SH-SY5Y cells. Following exposure to mercury, the concentration-dependent decrease in mitochondrial metabolic activity inversely correlated with oxidative stress intensity. MeHg was more toxic than HgCl2. Mercury-induced neuronal death was dependent on glutamate-mediated excitotoxicity. Caffeine reduced the mercury-induced oxidative stress in glutamine-containing medium. IFN-γ treatment decreased cell viability and increased oxidative stress in glutamine-free medium, despite caffeine supplementation. Although caffeine exerted a protective effect against MeHg-induced toxicity with glutamate transmission, under co-stimulation with glutamine and IFN-γ, caffeine decreased the MeHg-induced average oxidative stress only by half. Thereby, our data indicate that the IFN-γ stimulation of mercury-exposed dopaminergic neurons in neuroinflammatory diseases may diminish the neuroprotective effects of caffeine.

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Section: Discussionmentioning

confidence: 99%

Glutamate-mediated effects of caffeine and interferon-γ on mercury-induced toxicity

Engin

Golokhvast

et al. 2017

International Journal of Molecular Medicine

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“…This may indicate a substrate competition between Gln and Glu for reductive carboxylation which is known to be the major pathway for Gln utilization for lipogenic Acyl-CoA production (Leonardi et al 2012, Metallo et al 2012, Gameiro et al 2013). To be utilized for FA synthesis, Gln first needs to be converted to Glu by glutaminase which is localized in the mitochondria (Roberg et al 2010), thus adding an extra step for Gln utilization and defining Glu as a preferred substrate. In addition, the compartmentalization of Glu and Gln metabolism (McKenna et al 2000, Zielke et al 1998) will prevent mixing Glu and Gln product pools, thus each substrate might be channeled to FA synthesis through different enzymatic systems at different rates.…”

Section: Discussionmentioning

confidence: 99%

Fatty acid biosynthesis from glutamate and glutamine is specifically induced in neuronal cells under hypoxia

Brose

Marquardt

Golovko

2013

Journal of Neurochemistry

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Hypoxia is involved in many neuronal and non-neuronal diseases, and defining the mechanisms for tissue adaptation to hypoxia is critical for the understanding and treatment of these diseases. One mechanism for tissue adaptation to hypoxia is increased glutamine and/or glutamate (Gln/Glu) utilization. To address this mechanism, we determined total Gln/Glu incorporation into lipids and fatty acids in both primary neurons and a neuronal cell line under normoxic and hypoxic conditions and compared this to non-neuronal primary cells and non-neuronal cell lines. Incorporation of Gln/Glu into total lipids was dramatically and specifically increased under hypoxia in neuronal cells including both primary (2.0- and 3.0- fold for Gln and Glu, respectively) and immortalized cultures (3.5- and 8.0- fold for Gln and Glu, respectively), and 90% to 97% of this increase was accounted for by incorporation into fatty acids (FA) depending upon substrate and cell type. All other non-neuronal cells tested demonstrated decreased or unchanged FA synthesis from Gln/Glu under hypoxia. Consistent with these data, total FA mass was also increased in neuronal cells under hypoxia that was mainly accounted for by the increase in saturated and monounsaturated FA with carbon length from 14 to 24. Incorporation of FA synthesized from Gln/Glu was increased in all major lipid classes including cholesteryl esters, TAGs, DAGs, free FA, and phospholipids, with the highest rate of incorporation into TAGs. These results indicate that increased FA biosynthesis from Gln/Glu followed by esterification may be a neuronal specific pathway for adaptation to hypoxia.

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“…They are also richly endowed with mitochondria, which may supply the energy requirements for ionic pumps and participate in the glutamate-glutamine cycle, as they contain at least one form of its synthetic enzymes, the kidney-type of phosphate-activated glutaminase (PAG) (Laake te al., 1998), and at least one member of the amino-acid transporter family with high affinity for glutamine (Jenstad et al, 2009). PAG, which forms glutamate through glutamine deamidation, occurs in at least three isoforms (K-PAG, L-PAG, and GAC) having different kinetics and activation/inhibition properties; K-PAG and L-PAG are the products of two related genes, and GAC is probably an isoform of L-PAG lacking the C-terminus (Roberg et al, 2010). In brain there are mRNAs for all the three isoforms, but it is not known which of them is present in UBCs of the CR + and mGluR1α + subtypes.…”

Section: The Ultrastructure Of Ubcsmentioning

confidence: 99%

The unipolar brush cell: A remarkable neuron finally receiving deserved attention

Mugnaini

Sekerková

Martina

2011

Brain Research Reviews

161

152

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Unipolar brush cells (UBC) are small, glutamatergic neurons residing in the granular layer of the cerebellar cortex and the granule cell domain of the cochlear nuclear complex. Recent studies indicate that this neuronal class consists of three or more subsets characterized by distinct chemical phenotypes, as well as by intrinsic properties that may shape their synaptic responses and firing patterns. Yet, all UBCs have a unique morphology, as both the dendritic brush and the large endings of the axonal branches participate in the formation of glomeruli. Although UBCs and granule cells may share the same excitatory and inhibitory inputs, the two cell types are distinctively differentiated. Typically, whereas the granule cell has 4-5 dendrites that are innervated by different mossy fibers, and an axon that divides only once to form parallel fibers after ascending to the molecular layer, the UBC has but one short dendrite whose brush engages in synaptic contact with a single mossy fiber terminal, and an axon that branches locally in the granular layer; branches of UBC axons form a non-canonical, cortex-intrinsic category of mossy fibers synapsing with granule cells and other UBCs. This is thought to generate a feed-forward amplification of single mossy fiber afferent signals that would reach the overlying Purkinje cells via ascending granule cell axons and their parallel fibers.In sharp contrast to other classes of cerebellar neurons, UBCs are not distributed homogeneously across cerebellar lobules, and subsets of UBCs also show different, albeit overlapping, distributions. UBCs are conspicuously rare in the expansive lateral cerebellar areas targeted by the cortico-ponto-cerebellar pathway, while they are a constant component of the vermis and the flocculonodular lobe. The presence of UBCs in cerebellar regions involved in the sensorimotor processes that regulate body, head and eye position, as well as in regions of the cochlear nucleus that process sensorimotor information suggests a key role in these critical functions; it also invites further efforts to clarify the cellular biology of the UBCs and their specific functions in the neuronal microcircuits in which they are embedded. High density of UBCs in specific regions of the cerebellar cortex is a feature largely conserved across mammals and suggests an involvement of these neurons in fundamental aspects of the input/output organization as well as in clinical manifestation of focal cerebellar disease.

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Kinetics of a Novel Isoform of Phosphate Activated Glutaminase (PAG) in SH-SY5Y Neuroblastoma Cells

Cited by 7 publications

References 20 publications

Glutamate-mediated effects of caffeine and interferon-γ on mercury-induced toxicity

Glutamate-mediated effects of caffeine and interferon-γ on mercury-induced toxicity

Fatty acid biosynthesis from glutamate and glutamine is specifically induced in neuronal cells under hypoxia

The unipolar brush cell: A remarkable neuron finally receiving deserved attention

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