scholarly journals Aging differentially affects human skeletal muscle amino acid transporter expression when essential amino acids are ingested after exercise

2013 ◽  
Vol 32 (2) ◽  
pp. 273-280 ◽  
Author(s):  
Jared M. Dickinson ◽  
Micah J. Drummond ◽  
Jennifer R. Coben ◽  
Elena Volpi ◽  
Blake B. Rasmussen
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Amino Acid ◽  
Human Skeletal Muscle ◽  
Essential Amino Acids ◽  
Amino Acid Transporter ◽  
Acid Transporter ◽  
Transporter Expression

scholarly journals An increase in essential amino acid availability upregulates amino acid transporter expression in human skeletal muscle

2010 ◽  
Vol 298 (5) ◽  
pp. E1011-E1018 ◽  
Author(s):  
Micah J. Drummond ◽  
Erin L. Glynn ◽  
Christopher S. Fry ◽  
Kyle L. Timmerman ◽  
Elena Volpi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Amino Acid ◽  
Protein Expression ◽  
Human Skeletal Muscle ◽  
Amino Acid Transporter ◽  
Dependent Manner ◽  
Mtorc1 Signaling ◽  
Acid Transporter ◽  
Transporter Expression

Essential amino acids (EAA) stimulate skeletal muscle mammalian target of rapamycin complex 1 (mTORC1) signaling and protein synthesis. It has recently been reported that an increase in amino acid (AA) transporter expression during anabolic conditions is rapamycin-sensitive. The purpose of this study was to determine whether an increase in EAA availability increases AA transporter expression in human skeletal muscle. Muscle biopsies were obtained from the vastus lateralis of seven young adult subjects (3 male, 4 female) before and 1–3 h after EAA ingestion (10 g). Blood and muscle samples were analyzed for leucine kinetics using stable isotopic techniques. Quantitative RT-PCR, and immunoblotting were used to determine the mRNA and protein expression, respectively, of AA transporters and members of the general AA control pathway [general control nonrepressed (GCN2), activating transcription factor (ATF4), and eukaryotic initiation factor (eIF2) α-subunit (Ser52)]. EAA ingestion increased blood leucine concentration, delivery of leucine to muscle, transport of leucine from blood into muscle, intracellular muscle leucine concentration, ribosomal protein S6 (Ser240/244) phosphorylation, and muscle protein synthesis. This was followed with increased L-type AA transporter (LAT1), CD98, sodium-coupled neutral AA transporter (SNAT2), and proton-coupled amino acid transporter (PAT1) mRNA expression at 1 h ( P < 0.05) and modest increases in LAT1 protein expression (3 h post-EAA) and SNAT2 protein expression (2 and 3 h post-EAA, P < 0.05). Although there were no changes in GCN2 expression and eIF2α phosphorylation, ATF4 protein expression reached significance by 2 h post-EAA ( P < 0.05). We conclude that an increase in EAA availability upregulates human skeletal muscle AA transporter expression, perhaps in an mTORC1-dependent manner, which may be an adaptive response necessary for improved AA intracellular delivery.

scholarly journals Characterisation of L-Type Amino Acid Transporter 1 (LAT1) Expression in Human Skeletal Muscle by Immunofluorescent Microscopy

Nutrients ◽  
2017 ◽  
Vol 10 (1) ◽  
pp. 23 ◽  
Author(s):  
Nathan Hodson ◽  
Thomas Brown ◽  
Sophie Joanisse ◽  
Nick Aguirre ◽  
Daniel West ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amino Acid ◽  
Human Skeletal Muscle ◽  
Amino Acid Transporter ◽  
Immunofluorescent Microscopy ◽  
Acid Transporter

scholarly journals The L-Type Amino Acid Transporter LAT1—An Emerging Target in Cancer

2019 ◽  
Vol 20 (10) ◽  
pp. 2428 ◽  
Author(s):  
Pascal Häfliger ◽  
Roch-Philippe Charles
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cancer Cells ◽  
Cell Mass ◽  
Essential Amino Acids ◽  
Amino Acid Transporter ◽  
Membrane Transporters ◽  
Preclinical Studies ◽  
Acid Transporter

Chronic proliferation is a major hallmark of tumor cells. Rapidly proliferating cancer cells are highly dependent on nutrients in order to duplicate their cell mass during each cell division. In particular, essential amino acids are indispensable for proliferating cancer cells. Their uptake across the cell membrane is tightly controlled by membrane transporters. Among those, the L-type amino acid transporter LAT1 (SLC7A5) has been repeatedly found overexpressed in a vast variety of cancers. In this review, we summarize the most recent advances in our understanding of the role of LAT1 in cancer and highlight preclinical studies and drug developments underlying the potential of LAT1 as therapeutic target.

scholarly journals Ubiquitylation and endocytosis of the human LAT1/SLC7A5 amino acid transporter

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Céline Barthelemy ◽  
Bruno André
Keyword(s):  
Amino Acids ◽  
Plasma Membrane ◽  
Protein Kinase C ◽  
Amino Acid ◽  
Ubiquitin Ligase ◽  
Essential Amino Acids ◽  
Amino Acid Transporter ◽  
Kinase C ◽  
Acid Transporter ◽  
Mtorc1 Activation

AbstractThe human L-type amino acid transporter 1 (LAT1), also known as SLC7A5, catalyzes the transport of large neutral amino acids across the plasma membrane. As the main transporter of several essential amino acids, notably leucine, LAT1 plays an important role in mTORC1 activation. Furthermore, it is overexpressed in various types of cancer cells, where it contributes importantly to sustained growth. Despite the importance of LAT1 in normal and tumor cells, little is known about the mechanisms that might control its activity, for example by promoting its downregulation via endocytosis. Here we report that in HeLa cells, activation of protein kinase C by phorbol 12-myristate 13-acetate (PMA) triggers efficient endocytosis and degradation of LAT1. Under these conditions we found LAT1 downregulation to correlate with increased LAT1 ubiquitylation. This modification was considerably reduced in cells depleted of the Nedd4-2 ubiquitin ligase. By systematically mutagenizing the residues of the LAT1 cytosolic tails, we identified a group of three close lysines (K19, K25, K30) in the N-terminal tail that are important for PMA-induced ubiquitylation and downregulation. Our study thus unravels a mechanism of induced endocytosis of LAT1 elicited by Nedd4-2-mediated ubiquitylation of the transporter’s N-terminal tail.

scholarly journals The Regulation and Function of the L-Type Amino Acid Transporter 1 (LAT1) in Cancer

2018 ◽  
Vol 19 (8) ◽  
pp. 2373 ◽  
Author(s):  
Travis Salisbury ◽  
Subha Arthur
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cancer Cells ◽  
Amino Acid Uptake ◽  
Essential Amino Acids ◽  
Amino Acid Transporter ◽  
Amino Acid Transporters ◽  
Acid Uptake ◽  
Cancer Pathways ◽  
Acid Transporter

The progression of cancer is associated with increases in amino acid uptake by cancer cells. Upon their entry into cells through specific transporters, exogenous amino acids are used to synthesize proteins, nucleic acids and lipids and to generate ATP. The essential amino acid leucine is also important for maintaining cancer-associated signaling pathways. By upregulating amino acid transporters, cancer cells gain greater access to exogenous amino acids to support chronic proliferation, maintain metabolic pathways, and to enhance certain signal transduction pathways. Suppressing cancer growth by targeting amino acid transporters will require an in-depth understanding of how cancer cells acquire amino acids, in particular, the transporters involved and which cancer pathways are most sensitive to amino acid deprivation. L-Type Amino Acid Transporter 1 (LAT1) mediates the uptake of essential amino acids and its expression is upregulated during the progression of several cancers. We will review the upstream regulators of LAT1 and the downstream effects caused by the overexpression of LAT1 in cancer cells.

scholarly journals Bed rest impairs skeletal muscle amino acid transporter expression, mTORC1 signaling, and protein synthesis in response to essential amino acids in older adults

2012 ◽  
Vol 302 (9) ◽  
pp. E1113-E1122 ◽  
Author(s):  
Micah J. Drummond ◽  
Jared M. Dickinson ◽  
Christopher S. Fry ◽  
Dillon K. Walker ◽  
David M. Gundermann ◽  
...  
Keyword(s):  
Older Adults ◽  
Amino Acid ◽  
Protein Content ◽  
Bed Rest ◽  
Essential Amino Acids ◽  
Amino Acid Transporter ◽  
Transporter Protein ◽  
Mtorc1 Signaling ◽  
Acid Transporter ◽  
Transporter Expression

Skeletal muscle atrophy during bed rest is attributed, at least in part, to slower basal muscle protein synthesis (MPS). Essential amino acids (EAA) stimulate mammalian target of rapamycin (mTORC1) signaling, amino acid transporter expression, and MPS and are necessary for muscle mass maintenance, but there are no data on the effect of inactivity on this anabolic mechanism. We hypothesized that bed rest decreases muscle mass in older adults by blunting the EAA stimulation of MPS through reduced mTORC1 signaling and amino acid transporter expression in older adults. Six healthy older adults (67 ± 2 yr) participated in a 7-day bed rest study. We used stable isotope tracers, Western blotting, and real-time qPCR to determine the effect of bed rest on MPS, muscle mTORC1 signaling, and amino acid transporter expression and content in the postabsorptive state and after acute EAA ingestion. Bed rest decreased leg lean mass by ∼4% ( P < 0.05) and increased postabsorptive mTOR protein ( P < 0.05) levels while postabsorptive MPS was unchanged ( P > 0.05). Before bed rest acute EAA ingestion increased MPS, mTOR (Ser2448), S6 kinase 1 (Thr389, Thr421/Ser424), and ribosomal protein S6 (Ser240/244) phosphorylation, activating transcription factor 4, L-type amino acid transporter 1 and sodium-coupled amino acid transporter 2 protein content ( P < 0.05). However, bed rest blunted the EAA-induced increase in MPS, mTORC1 signaling, and amino acid transporter protein content. We conclude that bed rest in older adults significantly attenuated the EAA-induced increase in MPS with a mechanism involving reduced mTORC1 signaling and amino acid transporter protein content. Together, our data suggest that a blunted EAA stimulation of MPS may contribute to muscle loss with inactivity in older persons.

scholarly journals Neutral amino acid transporter ASCT2 displays substrate-induced Na+ exchange and a substrate-gated anion conductance

2000 ◽  
Vol 346 (3) ◽  
pp. 705-710 ◽  
Author(s):  
Angelika BRÖER ◽  
Carsten WAGNER ◽  
Florian LANG ◽  
Stefan BRÖER
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Anion Channel ◽  
Amino Acid Transporter ◽  
Neutral Amino Acid ◽  
Xenopus Laevis Oocytes ◽  
Anion Conductance ◽  
Neutral Amino Acid Transporter ◽  
Inward Currents ◽  
Acid Transporter

The neutral amino acid transporter ASCT2 mediates electroneutral obligatory antiport but at the same time requires Na+ for its function. To elucidate the mechanism, ASCT2 was expressed in Xenopus laevis oocytes and transport was analysed by flux studies and two-electrode voltage clamp recordings. Flux studies with 22NaCl indicated that the uptake of one molecule of glutamine or alanine is accompanied by the uptake of four to seven Na+ ions. Similarly to the transport of amino acids, the Na+ uptake was mediated by an obligatory Na+ exchange mechanism that depended on the presence of amino acids but was not stoichiometrically coupled to the amino acid transport. Other cations could not replace Na+ in this transport mechanism. When NaCl was replaced by NaSCN in the transport buffer, the superfusion of oocytes with amino acid substrates resulted in large inward currents, indicating the presence of a substrate-gated anion channel in the ASCT2 transporter. The Km for glutamine derived from these experiments is in good agreement with the Km derived from flux studies; it varied between 40 and 90 μM at holding potentials of -60 and -20 mV respectively. The permeability of the substrate-gated anion conductance decreased in the order SCN- NO3- > I- > Cl- and also required the presence of Na+.

scholarly journals Prognostic significance of amino-acid transporter expression (LAT1, ASCT2, and xCT) in surgically resected tongue cancer

2014 ◽  
Vol 110 (10) ◽  
pp. 2506-2513 ◽  
Author(s):  
M Toyoda ◽  
K Kaira ◽  
Y Ohshima ◽  
N S Ishioka ◽  
M Shino ◽  
...  
Keyword(s):  
Amino Acid ◽  
Tongue Cancer ◽  
Prognostic Significance ◽  
Amino Acid Transporter ◽  
Acid Transporter ◽  
Transporter Expression
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