Protein Kinase C Phosphorylates the System N Glutamine Transporter SN1 (Slc38a3) and Regulates Its Membrane Trafficking and Degradation

Nissen‐Meyer, Lise Sofie Haug; Chaudhry, Farrukh A.

doi:10.3389/fendo.2013.00138

Cited by 22 publications

(19 citation statements)

References 72 publications

(101 reference statements)

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“…In contrast to fibroblasts and leukocytes, levels of NAD + did not increase upon supplementation of glutamine or nicotinamide to the culture medium. As there are families of glutamine transporters with differential age-and cell-specific localization (Boulland et al 2003;Nissen-Meyer and Chaudhry 2013) these data suggest that PBSCs may lack proper glutamine transporters at this stage (as they are immature and undifferentiated) and thus exogenous glutamine may not contribute to stimulation of NAD + synthesis. Similarly, transport of nicotinamide into PBSC may have been hampered due to lack of the necessary transport systems.…”

Section: Discussionmentioning

confidence: 98%

Secondary NAD⁺ deficiency in the inherited defect of glutamine synthetase

Ibrahim

Stucki

et al. 2015

J of Inher Metab Disea

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Glutamine synthetase (GS) deficiency is an ultra-rare inborn error of amino acid metabolism that has been described in only three patients so far. The disease is characterized by neonatal onset of severe encephalopathy, low levels of glutamine in blood and cerebrospinal fluid, chronic moderate hyperammonemia, and an overall poor prognosis in the absence of an effective treatment. Recently, enteral glutamine supplementation was shown to be a safe and effective therapy for this disease but there are no data available on the long-term effects of this intervention. The amino acid glutamine, severely lacking in this disorder, is central to many metabolic pathways in the human organism and is involved in the synthesis of nicotinamide adenine dinucleotide (NAD(+)) starting from tryptophan or niacin as nicotinate, but not nicotinamide. Using fibroblasts, leukocytes, and immortalized peripheral blood stem cells (PBSC) from a patient carrying a GLUL gene point mutation associated with impaired GS activity, we tested whether glutamine deficiency in this patient results in NAD(+) depletion and whether it can be rescued by supplementation with glutamine, nicotinamide or nicotinate. The present study shows that congenital GS deficiency is associated with NAD(+) depletion in fibroblasts, leukocytes and PBSC, which may contribute to the severe clinical phenotype of the disease. Furthermore, it shows that NAD(+) depletion can be rescued by nicotinamide supplementation in fibroblasts and leukocytes, which may open up potential therapeutic options for the treatment of this disorder.

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Section: Discussionmentioning

confidence: 98%

Secondary NAD⁺ deficiency in the inherited defect of glutamine synthetase

Ibrahim

Stucki

et al. 2015

J of Inher Metab Disea

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“…For that reason it should be considered that these transporters may be subject to post translational regulation, a mechanism that has been broadly described for SN1 (Karinch et al, 2002;Nissen-Meyer and Chaudhry, 2013). Accordingly, different studies observed that SN1 is directly phosphorylated by the enzymes PKCα, PKCγ, and PKCδ (Nissen-Meyer et al, 2011;Sidoryk-Wegrzynowicz et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…In the context of glutamine transfer between neurons and astrocytes, the small neutral amino acid transporters play an important role in the communication between these cells and thus, they are fundamental for the maintenance of the glutamate/GABA-glutamine cycle (Nissen-Meyer and Chaudhry, 2013). The SN1 and SN2 isoforms, also known as SNAT3 and SNAT5, are electroneutral transporters functioning as a Na + -glutamine symporter and H + anti-porter related to glutamine efflux from astrocytes (Chaudhry et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

Leke

Escobar

Rao

et al. 2015

Neurochemistry International

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Rama Rao, Kakulavarapu V.; Silveira, Themis Reverbel; Norenberg, Michael D.; and Schousboe, Arne, "Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy" (2015 Keywords:Chronic hepatic encephalopathy Glutamine transporters Glutamine GABA A B S T R A C THepatic encephalopathy (HE) is a neuropsychiatric disorder that occurs due to acute and chronic liver diseases, the hallmark of which is the increased levels of ammonia and subsequent alterations in glutamine synthesis, i.e. conditions associated with the pathophysiology of HE. Under physiological conditions, glutamine is fundamental for replenishment of the neurotransmitter pools of glutamate and GABA. The different isoforms of glutamine transporters play an important role in the transfer of this amino acid between astrocytes and neurons. A disturbance in the GABA biosynthetic pathways has been described in bile duct ligated (BDL) rats, a well characterized model of chronic HE. Considering that glutamine is important for GABA biosynthesis, altered glutamine transport and the subsequent glutamate/GABA-glutamine cycle efficacy might influence these pathways. Given this potential outcome, the aim of the present study was to investigate whether the expression of the glutamine transporters SAT1, SAT2, SN1 and SN2 would be affected in chronic HE. We verified that mRNA expression of the neuronal glutamine transporters SAT1 and SAT2 was found unaltered in the cerebral cortex of BDL rats. Similarly, no changes were found in the mRNA level for the astrocytic transporter SN1, whereas the gene expression of SN2 was increased by two-fold in animals with chronic HE. However, SN2 protein immuno-reactivity did not correspond with the increase in gene transcription since it remained unaltered. These data indicate that the expression of the glutamine transporter isoforms is unchanged during chronic HE, and thus likely not to participate in the pathological mechanisms related to the imbalance in the GABAergic neurotransmitter system observed in this neurologic condition.

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“…In addition, gamma-aminobutyric acid (GABA), the inhibitory neurotransmitter that regulates neuronal excitability, is also synthesized through the glutamine-glutamate cycle. GABA synthesis and function is beyond the scope of this review, but see [100,98,101] for review of GABA and the glutamine-glutamate cycle.…”

Section: Glutamate Release and Uptake In The Non-pathological Brainmentioning

confidence: 99%

Glutamate transporters in the biology of malignant gliomas

Robert

Sontheimer

2013

Cell. Mol. Life Sci.

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Malignant gliomas are relentless tumors that offer a dismal clinical prognosis. They develop many biological advantages that allow them to grow and survive in the unique environment of the brain. The glutamate transporters System xc− and Excitatory Amino Acid Transporters (EAAT) are emerging as key players in the biology and malignancy of these tumors. Gliomas manipulate glutamate transporter expression and function to alter glutamate homeostasis in the brain, which supports their own growth, invasion, and survival. As a consequence, malignant cells are able to quickly destroy and invade surrounding normal brain. Recent findings are painting a larger picture of these transporters in glioma biology, and as such are providing opportunities for clinical intervention for patients. This review will detail the current understanding of glutamate transporters in the biology of malignant gliomas and highlight some of the unique aspects of these tumors that make them so devastating and difficult to treat.

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Protein Kinase C Phosphorylates the System N Glutamine Transporter SN1 (Slc38a3) and Regulates Its Membrane Trafficking and Degradation

Cited by 22 publications

References 72 publications

Secondary NAD⁺ deficiency in the inherited defect of glutamine synthetase

Secondary NAD⁺ deficiency in the inherited defect of glutamine synthetase

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

Glutamate transporters in the biology of malignant gliomas

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Protein Kinase C Phosphorylates the System N Glutamine Transporter SN1 (Slc38a3) and Regulates Its Membrane Trafficking and Degradation

Cited by 22 publications

References 72 publications

Secondary NAD+ deficiency in the inherited defect of glutamine synthetase

Secondary NAD+ deficiency in the inherited defect of glutamine synthetase

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

Glutamate transporters in the biology of malignant gliomas

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Secondary NAD⁺ deficiency in the inherited defect of glutamine synthetase

Secondary NAD⁺ deficiency in the inherited defect of glutamine synthetase