scholarly journals Amino acid transporters: roles in amino acid sensing and signalling in animal cells

2003 ◽  
Vol 373 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Russell HYDE ◽  
Peter M. TAYLOR ◽  
Harinder S. HUNDAL
Keyword(s):  
Gene Expression ◽  
Amino Acids ◽  
Amino Acid ◽  
Nutrient Availability ◽  
Cellular Response ◽  
Amino Acid Transporters ◽  
Animal Cells ◽  
Amino Acid Availability ◽  
Altered Gene ◽  
Amino Acid Sensing

Amino acid availability regulates cellular physiology by modulating gene expression and signal transduction pathways. However, although the signalling intermediates between nutrient availability and altered gene expression have become increasingly well documented, how eukaryotic cells sense the presence of either a nutritionally rich or deprived medium is still uncertain. From recent studies it appears that the intracellular amino acid pool size is particularly important in regulating translational effectors, thus, regulated transport of amino acids across the plasma membrane represents a means by which the cellular response to amino acids could be controlled. Furthermore, evidence from studies with transportable amino acid analogues has demonstrated that flux through amino acid transporters may act as an initiator of nutritional signalling. This evidence, coupled with the substrate selectivity and sensitivity to nutrient availability classically associated with amino acid transporters, plus the recent discovery of transporter-associated signalling proteins, demonstrates a potential role for nutrient transporters as initiators of cellular nutrient signalling. Here, we review the evidence supporting the idea that distinct amino acid “receptors” function to detect and transmit certain nutrient stimuli in higher eukaryotes. In particular, we focus on the role that amino acid transporters may play in the sensing of amino acid levels, both directly as initiators of nutrient signalling and indirectly as regulators of external amino acid access to intracellular receptor/signalling mechanisms.

Increases in circulating amino acids with in-feed antibiotics correlated with gene expression of intestinal amino acid transporters in piglets

Amino Acids ◽  
2017 ◽  
Vol 49 (9) ◽  
pp. 1587-1599 ◽  
Author(s):  
Miao Yu ◽  
Chunlong Mu ◽  
Yuxiang Yang ◽  
Chuanjian Zhang ◽  
Yong Su ◽  
...  
Keyword(s):  
Gene Expression ◽  
Amino Acids ◽  
Amino Acid ◽  
Amino Acid Transporters

scholarly journals Amino acid transceptors: gate keepers of nutrient exchange and regulators of nutrient signaling

2009 ◽  
Vol 296 (4) ◽  
pp. E603-E613 ◽  
Author(s):  
Harinder S. Hundal ◽  
Peter M. Taylor
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Dual Function ◽  
Amino Acid Transporters ◽  
Coupled Transport ◽  
Extracellular Milieu ◽  
Mammalian Cell Lines ◽  
Amino Acid Availability ◽  
Intracellular Amino Acid ◽  
Extracellular Amino Acid

Amino acid transporters at the surface of cells are in an ideal location to relay nutritional information, as well as nutrients themselves, to the cell interior. These transporters are able to modulate signaling downstream of intracellular amino acid receptors by regulating intracellular amino acid concentrations through processes of coupled transport. The concept of dual-function amino acid transporter/receptor (or “transceptor”) proteins is well established in primitive eukaryotes such as yeast, where detection of extracellular amino acid deficiency leads to upregulation of proteins involved in biosynthesis and transport of the deficient amino acid(s). The evolution of the “extracellular milieu” and nutrient-regulated endocrine controls in higher eukaryotes, alongside their frequent inability to synthesize all proteinaceous amino acids (and, hence, the requirement for indispensable amino acids in their diet), appears to have lessened the priority of extracellular amino acid sensing as a stimulus for metabolic signals. Nevertheless, recent studies of amino acid transporters in flies and mammalian cell lines have revealed perhaps unanticipated “echoes” of these transceptor functions, which are revealed by cellular stresses (notably starvation) or gene modification/silencing. APC-transporter superfamily members, including slimfast, path, and SNAT2 all appear capable of sensing and signaling amino acid availability to the target of rapamycin (TOR) pathway, possibly through PI 3-kinase-dependent mechanisms. We hypothesize (by extrapolation from knowledge of the yeast Ssy1 transceptor) that, at least for SNAT2, the transceptor discriminates between extracellular and intracellular amino acid stimuli when evoking a signal.

scholarly journals Amino acids inhibit Agrp gene expression via an mTOR-dependent mechanism

2007 ◽  
Vol 293 (1) ◽  
pp. E165-E171 ◽  
Author(s):  
Christopher D. Morrison ◽  
Xiaochun Xi ◽  
Christy L. White ◽  
Jianping Ye ◽  
Roy J. Martin
Keyword(s):  
Gene Expression ◽  
Amino Acids ◽  
Amino Acid ◽  
Food Intake ◽  
Mtor Signaling ◽  
Acid Mixture ◽  
Mrna Levels ◽  
Amino Acid Availability ◽  
The Brain ◽  
Amino Acid Concentrations

Metabolic fuels act on hypothalamic neurons to regulate feeding behavior and energy homeostasis, but the signaling mechanisms mediating these effects are not fully clear. Rats placed on a low-protein diet (10% of calories) exhibited increased food intake ( P < 0.05) and hypothalamic Agouti-related protein ( Agrp) gene expression ( P = 0.002). Direct intracerebroventricular injection of either an amino acid mixture (RPMI 1640) or leucine alone (1 μg) suppressed 24-h food intake ( P < 0.05), indicating that increasing amino acid concentrations within the brain is sufficient to suppress food intake. To define a cellular mechanism for these direct effects, GT1–7 hypothalamic cells were exposed to low amino acids for 16 h. Decreasing amino acid availability increased Agrp mRNA levels in GT1–7 cells ( P < 0.01), and this effect was attenuated by replacement of the amino acid leucine ( P < 0.05). Acute exposure to elevated amino acid concentrations increased ribosomal protein S6 kinase phosphorylation via a rapamycin-sensitive mechanism, suggesting that amino acids directly stimulated mammalian target of rapamycin (mTOR) signaling. To test whether mTOR signaling contributes to amino acid inhibition of Agrp gene expression, GT1–7 cells cultured in either low or high amino acids for 16 h and were also treated with rapamcyin (50 nM). Rapamycin treatment increased Agrp mRNA levels in cells exposed to high amino acids ( P = 0.01). Taken together, these observations indicate that amino acids can act within the brain to inhibit food intake and that a direct, mTOR-dependent inhibition of Agrp gene expression may contribute to this effect.

Differential cystine and dibasic amino acid handling after loss of function of the amino acid transporter b0,+AT (Slc7a9) in mice

2013 ◽  
Vol 305 (12) ◽  
pp. F1645-F1655 ◽  
Author(s):  
Andrea Di Giacopo ◽  
Isabel Rubio-Aliaga ◽  
Alessandra Cantone ◽  
Ferruh Artunc ◽  
Rexhep Rexhepaj ◽  
...  
Keyword(s):  
Gene Expression ◽  
Amino Acids ◽  
Amino Acid ◽  
Membrane Vesicle ◽  
Fractional Excretion ◽  
Amino Acid Transporters ◽  
Type I ◽  
Loss Of Function ◽  
Dibasic Amino Acid ◽  
Knockout Animals

Cystinuria is an autosomal recessive disease caused by mutations in SLC3A1 ( rBAT) and SLC7A9 ( b 0,+ AT). Gene targeting of the catalytic subunit ( Slc7a9) in mice leads to excessive excretion of cystine, lysine, arginine, and ornithine. Here, we studied this non-type I cystinuria mouse model using gene expression analysis, Western blotting, clearance, and brush-border membrane vesicle (BBMV) uptake experiments to further characterize the renal and intestinal consequences of losing Slc7a9 function. The electrogenic and BBMV flux studies in the intestine suggested that arginine and ornithine are transported via other routes apart from system b0,+. No remarkable gene expression changes were observed in other amino acid transporters and the peptide transporters in the intestine and kidney. Furthermore, the glomerular filtration rate (GFR) was reduced by 30% in knockout animals compared with wild-type animals. The fractional excretion of arginine was increased as expected (∼100%), but fractional excretions of lysine (∼35%), ornithine (∼16%), and cystine (∼11%) were less affected. Loss of function of b0,+AT reduced transport of cystine and arginine in renal BBMVs and completely abolished the exchanger activity of dibasic amino acids with neutral amino acids. In conclusion, loss of Slc7a9 function decreases the GFR and increases the excretion of several amino acids to a lesser extent than expected with no clear regulation at the mRNA and protein level of alternative transporters and no increased renal epithelial uptake. These observations indicate that transporters located in distal segments of the kidney and/or metabolic pathways may partially compensate for Slc7a9 loss of function.

scholarly journals Regulation of Amino Acid Transport in Saccharomyces cerevisiae

2019 ◽  
Vol 83 (4) ◽  
Author(s):  
Frans Bianchi ◽  
Joury S. van’t Klooster ◽  
Stephanie J. Ruiz ◽  
Bert Poolman
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Amino Acids ◽  
Amino Acid ◽  
De Novo ◽  
Amino Acid Transporters ◽  
Content Type ◽  
Growth And Survival ◽  
Amino Acid Homeostasis ◽  
Underlying Mechanisms ◽  
Amino Acid Sensing

SUMMARY We review the mechanisms responsible for amino acid homeostasis in Saccharomyces cerevisiae and other fungi. Amino acid homeostasis is essential for cell growth and survival. Hence, the de novo synthesis reactions, metabolic conversions, and transport of amino acids are tightly regulated. Regulation varies from nitrogen pool sensing to control by individual amino acids and takes place at the gene (transcription), protein (posttranslational modification and allostery), and vesicle (trafficking and endocytosis) levels. The pools of amino acids are controlled via import, export, and compartmentalization. In yeast, the majority of the amino acid transporters belong to the APC (amino acid-polyamine-organocation) superfamily, and the proteins couple the uphill transport of amino acids to the electrochemical proton gradient. Although high-resolution structures of yeast amino acid transporters are not available, homology models have been successfully exploited to determine and engineer the catalytic and regulatory functions of the proteins. This has led to a further understanding of the underlying mechanisms of amino acid sensing and subsequent downregulation of transport. Advances in optical microscopy have revealed a new level of regulation of yeast amino acid transporters, which involves membrane domain partitioning. The significance and the interrelationships of the latest discoveries on amino acid homeostasis are put in context.

Prolyl hydroxylases as regulators of cell metabolism

2009 ◽  
Vol 37 (1) ◽  
pp. 291-294 ◽  
Author(s):  
Houda Boulahbel ◽  
Raúl V. Durán ◽  
Eyal Gottlieb
Keyword(s):  
Amino Acid ◽  
Cellular Response ◽  
Oxygen Sensing ◽  
Cell Metabolism ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
Oxygen Depletion ◽  
Animal Cells ◽  
Prolyl Hydroxylases ◽  
Amino Acid Availability

Cellular response to oxygen depletion is mediated by HIF (hypoxia-inducible factor). HIF is a heterodimer consisting of a constitutively expressed subunit (HIFβ) and an oxygen-regulated subunit (HIFα). HIFα stability is regulated by prolyl hydroxylation by PHD (prolyl hydroxylase domain-containing protein) family members. PHD activity depends on the availability of molecular oxygen, making PHDs the oxygen-sensing system in animal cells. However, PHDs have recently been shown to respond to stimuli other than oxygen, such as 2-oxoglutarate (α-ketoglutarate), succinate or fumarate, as illustrated by the pseudo-hypoxic response in succinate dehydrogenase- or fumarate dehydrogenase-deficient tumours. Moreover, HIFα is not the sole PHD effector, suggesting that PHDs have functions that extend beyond oxygen sensing. Currently, we are investigating the role of PHDs in the cellular response to amino acid deprivation, a process regulated by mTOR (mammalian target of rapamycin). The precise mechanism whereby amino acids are signalling to mTOR is not fully understood. Given that 2-oxoglutarate is a limiting co-substrate for PHD activity during normoxia and that 2-oxoglutarate levels depend on amino acid availability, it is possible that PHD activity depends not only on oxygen, but also on amino acid availability, suggesting a global metabolic sensor function for PHDs which could be signalling not only to HIF, but also to mTOR.

Transporters for Cationic Amino Acids in Animal Cells: Discovery, Structure, and Function

1998 ◽  
Vol 78 (2) ◽  
pp. 487-545 ◽  
Author(s):  
R. DEVÉS ◽  
C. A. R. BOYD
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Structure And Function ◽  
Xenopus Laevis Oocytes ◽  
Amino Acid Transporters ◽  
Cdna Clones ◽  
Animal Cells ◽  
Cationic Amino Acid ◽  
Cationic Amino Acids ◽  
And Function

Devés, R., and C. A. R. Boyd. Transporters for Cationic Amino Acids in Animal Cells: Discovery, Structure, and Function. Physiol. Rev. 78: 487–545, 1998. — The structure and function of the four cationic amino acid transporters identified in animal cells are discussed. The systems differ in specificity, cation dependence, and physiological role. One of them, system y+, is selective for cationic amino acids, whereas the others (B0,+, b0,+, and y+L) also accept neutral amino acids. In recent years, cDNA clones related to these activities have been isolated. Thus two families of proteins have been identified: 1) CAT or cationic amino acid transporters and 2) BAT or broad-scope transport proteins. In the CAT family, three genes encode for four different isoforms [CAT-1, CAT-2A, CAT-2(B) and CAT-3]; these are ∼70-kDa proteins with multiple transmembrane segments ( 12 – 14 ), and despite their structural similarity, they differ in tissue distribution, kinetics, and regulatory properties. System y+is the expression of the activity of CAT transporters. The BAT family includes two isoforms (rBAT and 4F2hc); these are 59- to 78-kDa proteins with one to four membrane-spanning segments, and it has been proposed that these proteins act as transport regulators. The expression of rBAT and 4F2hc induces system b0,+and system y+L activity in Xenopus laevis oocytes, respectively. The roles of these transporters in nutrition, endocrinology, nitric oxide biology, and immunology, as well as in the genetic diseases cystinuria and lysinuric protein intolerance, are reviewed. Experimental strategies, which can be used in the kinetic characterization of coexpressed transporters, are also discussed.

scholarly journals Amino Acid Sensing in Metabolic Homeostasis and Health

2020 ◽  
Author(s):  
Xiaoming Hu ◽  
Feifan Guo
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Metabolic Regulation ◽  
Metabolic Diseases ◽  
Nutrient Sensing ◽  
The Body ◽  
Bioactive Molecules ◽  
Metabolic Homeostasis ◽  
Amino Acid Availability ◽  
Amino Acid Sensing

Abstract Sensing and responding to changes in nutrient levels, including those of glucose, lipids, and amino acids, by the body is necessary for survival. Accordingly, perturbations in nutrient sensing are tightly linked with human pathologies, particularly metabolic diseases such as obesity, type 2 diabetes mellitus, and other complications of metabolic syndromes. The conventional view is that amino acids are fundamental elements for protein and peptide synthesis, while recent studies have revealed that amino acids are also important bioactive molecules that play key roles in signaling pathways and metabolic regulation. Different pathways that sense intracellular and extracellular levels of amino acids are integrated and coordinated at the organismal level, and, together, these pathways maintain whole metabolic homeostasis. In this review, we discuss the studies describing how important sensing signals respond to amino acid availability and how these sensing mechanisms modulate metabolic processes, including energy, glucose, and lipid metabolism. We further discuss whether dysregulation of amino acid sensing signals can be targeted to promote metabolic disorders, and discuss how to translate these mechanisms to treat human diseases. This review will help to enhance our overall understanding of the correlation between amino acid sensing and metabolic homeostasis, which have important implications for human health.

scholarly journals Complementary α-arrestin-ubiquitin ligase complexes control nutrient transporter endocytosis in response to amino acids

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Vasyl Ivashov ◽  
Johannes Zimmer ◽  
Sinead Schwabl ◽  
Jennifer Kahlhofer ◽  
Sabine Weys ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Ubiquitin Ligase ◽  
Amino Acid Transporters ◽  
General Amino Acid Control ◽  
Amino Acid Availability ◽  
Genome Wide ◽  
A Genome ◽  
Lysine Residues ◽  
Nutrient Transporter

How cells adjust nutrient transport across their membranes is incompletely understood. Previously, we have shown that S. cerevisiae broadly re-configures the nutrient transporters at the plasma membrane in response to amino acid availability, through endocytosis of sugar- and amino acid transporters (AATs) (Müller et al., 2015). A genome-wide screen now revealed that the selective endocytosis of four AATs during starvation required the α-arrestin family protein Art2/Ecm21, an adaptor for the ubiquitin ligase Rsp5, and its induction through the general amino acid control pathway. Art2 uses a basic patch to recognize C-terminal acidic sorting motifs in AATs and thereby instructs Rsp5 to ubiquitinate proximal lysine residues. When amino acids are in excess, Rsp5 instead uses TORC1-activated Art1 to detect N-terminal acidic sorting motifs within the same AATs, which initiates exclusive substrate-induced endocytosis. Thus, amino acid excess or starvation activate complementary α-arrestin-Rsp5-complexes to control selective endocytosis and adapt nutrient acquisition.

scholarly journals A Ragulator–BORC interaction controls lysosome positioning in response to amino acid availability

2017 ◽  
Vol 216 (12) ◽  
pp. 4183-4197 ◽  
Author(s):  
Jing Pu ◽  
Tal Keren-Kaplan ◽  
Juan S. Bonifacino
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Cellular Response ◽  
Mammalian Target Of Rapamycin ◽  
Small Gtpase ◽  
Regulatory Effect ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Amino Acid Availability ◽  
Amino Acid Depletion

Lysosomes play key roles in the cellular response to amino acid availability. Depletion of amino acids from the medium turns off a signaling pathway involving the Ragulator complex and the Rag guanosine triphosphatases (GTPases), causing release of the inactive mammalian target of rapamycin complex 1 (mTORC1) serine/threonine kinase from the lysosomal membrane. Decreased phosphorylation of mTORC1 substrates inhibits protein synthesis while activating autophagy. Amino acid depletion also causes clustering of lysosomes in the juxtanuclear area of the cell, but the mechanisms responsible for this phenomenon are poorly understood. Herein we show that Ragulator directly interacts with BLOC-1–related complex (BORC), a multi-subunit complex previously found to promote lysosome dispersal through coupling to the small GTPase Arl8 and the kinesins KIF1B and KIF5B. Interaction with Ragulator exerts a negative regulatory effect on BORC that is independent of mTORC1 activity. Amino acid depletion strengthens this interaction, explaining the redistribution of lysosomes to the juxtanuclear area. These findings thus demonstrate that amino acid availability controls lysosome positioning through Ragulator-dependent, but mTORC1-independent, modulation of BORC.

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