The transport of glutamine into mammalian cells

McGivan, J D; Bungard, Claire I.

doi:10.2741/2109

Cited by 109 publications

(97 citation statements)

References 39 publications

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“…This neonatal peak in GS activity coincides with the period of terminal differentiation and nerve-induced growth of the myotubes (32). Because glutamine transport in skeletal muscle is electrogenic and dependent on innervation (33), the decline in GS activity may well reflect an innervation-dependent increase in the intracellular concentration of glutamine (34), which is known to decrease the halflife of GS protein (4 -6, 35). Cre expression in transgenic MCKCre striated muscle begins just prior to birth and reaches its maximal level only at ϳ10 days after birth (17).…”

Section: Discussionmentioning

confidence: 99%

Glutamine Synthetase in Muscle Is Required for Glutamine Production during Fasting and Extrahepatic Ammonia Detoxification

Hakvoort

Köhler³

et al. 2010

Journal of Biological Chemistry

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The main endogenous source of glutamine is de novo synthesis in striated muscle via the enzyme glutamine synthetase (GS). The mice in which GS is selectively but completely eliminated from striated muscle with the Cre-loxP strategy (GS-KO/M mice) are, nevertheless, healthy and fertile. Compared with controls, the circulating concentration and net production of glutamine across the hindquarter were not different in fed GS-KO/M mice. Only a ϳ3-fold higher escape of ammonia revealed the absence of GS in muscle. However, after 20 h of fasting, GS-KO/M mice were not able to mount the ϳ4-fold increase in glutamine production across the hindquarter that was observed in control mice. Instead, muscle ammonia production was ϳ5-fold higher than in control mice. The fasting-induced metabolic changes were transient and had returned to fed levels at 36 h of fasting. Glucose consumption and lactate and ketone-body production were similar in GS-KO/M and control mice. Challenging GS-KO/M and control mice with intravenous ammonia in stepwise increments revealed that normal muscle can detoxify ϳ2.5 mol ammonia/g muscle⅐h in a muscle GS-dependent manner, with simultaneous accumulation of urea, whereas GS-KO/M mice responded with accumulation of glutamine and other amino acids but not urea. These findings demonstrate that GS in muscle is dispensable in fed mice but plays a key role in mounting the adaptive response to fasting by transiently facilitating the production of glutamine. Furthermore, muscle GS contributes to ammonia detoxification and urea synthesis. These functions are apparently not vital as long as other organs function normally.Glutamine is among the most abundant free amino acids in mammals. Almost 90% of the daily glutamine production originates from endogenous sources, because 30 -35% of all nitrogen derived from protein catabolism is transported in the form of glutamine (1, 2). This glutamine can serve, after transport via the vasculature, as an oxidative fuel for enterocytes and immune cells, a precursor for purine and pyrimidine synthesis, a modulator of protein turnover, or an intermediate for gluconeogenesis and acid-base balance. The only enzyme capable of glutamine synthesis is glutamine synthetase (L-glutamate: ammonia ligase (ADP); EC 6.3.1.2). Because of the prominent role of glutamine in the interorgan transport of carbon and nitrogen, the plasma glutamine pool is turning over very rapidly (3). Glutamine tracer kinetic studies in humans have shown that ϳ50% of plasma glutamine is oxidized and that of the remainder, 10 -20% is used for gluconeogenesis, and most of the rest is used for protein synthesis and incorporation into macromolecules (2).Thus far, the irreversible GS 5 inhibitor methionine sulfoximine (MSO) was the tool of choice to interfere with cellular glutamine synthesis. Administration of MSO for 4 -6 days results in a 40 -50% decrease in plasma glutamine levels, a 55-65% decrease in intracellular muscle glutamine, and a 50% increase in muscle ammonia levels (4 -6). An inherent drawback of the...

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Section: Discussionmentioning

confidence: 99%

Glutamine Synthetase in Muscle Is Required for Glutamine Production during Fasting and Extrahepatic Ammonia Detoxification

Hakvoort

Köhler³

et al. 2010

Journal of Biological Chemistry

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“…SNAT1 is also responsible for the transport of neutral amino acids into or out of cells in mammals (McGivan and Bungard, 2007). So far, SNAT1 is recognized as a target for oncogene action because the amount of its mRNA is increased in human hepatocarcinoma cells.…”

Section: Gene Expressionmentioning

confidence: 99%

Growth of embryo and gene expression of nutrient transporters in the small intestine of the domestic pigeon (Columba livia)

Mingxia

Yang

et al. 2015

J. Zhejiang Univ. Sci. B

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Abstract:The objective of this study was to investigate the relationship between gene expression of nutrient (amino acid, peptide, sodium and proton) transporters in the small intestine and embryonic growth in domestic pigeons (Columba livia). One hundred and twenty-five fertilized eggs were randomly assigned into five groups and were incubated under optimal conditions (temperature of 38.1 °C and relative humidity of 55%). Twenty embryos/birds from each group were sacrificed by cervical dislocation on embryonic day (E) 9, 11, 13, 15 and day of hatch (DOH). The eggs, embryos (without yolk sac), and organs (head, brain, heart, liver, lungs, kidney, gizzard, small intestine, legs, and thorax) were dissected, cleaned, and weighed. Small intestine samples were collected for RNA isolation. The mRNA abundance of intestinal nutrient transporters was evaluated by real-time reverse transcription-polymerase chain reaction (RT-PCR). We classified these ten organs into four types according to the changes in relative weight during embryonic development. In addition, the gene expression of nutrient transporters was differentially regulated by embryonic day. AT, EAAT3, LAT4, PepT1, NHE2, NHE3, and y + LAT2 showed positive correlations with intestinal weight (0.80

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“…For this reason, it must be transported from the extracellular medium into the mitochondria of tumor cells by specific transporters in the plasma and mitochondrial inner membranes. 64 The mitochondrial transport of metabolites is usually one or two orders of magnitude faster than plasma-membrane-related transport. Studies using native vesicles isolated from the mitochondrial inner membrane confirmed the existence of a transport system with a high capacity and specificity for L-glutamine, showing cooperation and strong inhibition of some L-glutamine analogs.…”

Section: Glutamine Metabolismmentioning

confidence: 99%