scholarly journals Inhibitors of the Neutral Amino Acid Transporters ASCT1 and ASCT2 Are Effective in In Vivo Models of Schizophrenia and Visual Dysfunction

2018 ◽  
Vol 367 (2) ◽  
pp. 292-301 ◽  
Author(s):  
Yong-Xin Li ◽  
Jia-Ying Yang ◽  
Miguel Alcantara ◽  
Grigor Abelian ◽  
Ashutosh Kulkarni ◽  
...  
Keyword(s):  
Amino Acid ◽  
Neutral Amino Acid ◽  
Amino Acid Transporters ◽  
Visual Dysfunction ◽  
In Vivo Models

Hypoxic Stress Upregulates the Expression of Slc38a1 in Brown Adipocytes via Hypoxia-Inducible Factor-1α

Pharmacology ◽  
2017 ◽  
Vol 101 (1-2) ◽  
pp. 64-71 ◽  
Author(s):  
Tetsuhiro Horie ◽  
Kazuya Fukasawa ◽  
Takashi Iezaki ◽  
Gyujin Park ◽  
Yuki Onishi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Hypoxia Inducible Factor ◽  
Amino Acid Transporters ◽  
Hypoxic Stress ◽  
Gene Encoding ◽  
Brown Adipocytes ◽  
Hypoxia Inducible Factor 1Α ◽  
Brown Adipose

The availability of amino acid in the brown adipose tissue (BAT) has been shown to be altered under various conditions; however, little is known about the possible expression and pivotal role of amino acid transporters in BAT under physiological and pathological conditions. The present study comprehensively investigated whether amino acid transporters are regulated by obesogenic conditions in BAT in vivo. Moreover, we investigated the mechanism underlying the regulation of the expression of amino acid transporters by various stressors in brown adipocytes in vitro. The expression of solute carrier family 38 member 1 (Slc38a1; gene encoding sodium-coupled neutral amino acid transporter 1) was preferentially upregulated in the BAT of both genetic and acquired obesity mice in vivo. Moreover, the expression of Slc38a1 was induced by hypoxic stress through hypoxia-inducible factor-1α, which is a master transcription factor of the adaptive response to hypoxic stress, in brown adipocytes in vitro. These results indicate that Slc38a1 is an obesity-associated gene in BAT and a hypoxia-responsive gene in brown adipocytes.

scholarly journals Antagonists of the system L neutral amino acid transporter (LAT) promote endothelial adhesivity of human red blood cells

2017 ◽  
Vol 117 (07) ◽  
pp. 1402-1411 ◽  
Author(s):  
Laura Beth Mann Dosier ◽  
Vikram J. Premkumar ◽  
Hongmei Zhu ◽  
Izzet Akosman ◽  
Michael F. Wempe ◽  
...  
Keyword(s):  
Amino Acid ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Amino Acid Transporter ◽  
Neutral Amino Acid ◽  
Neutral Amino Acid Transporter ◽  
System L

SummaryThe system L neutral amino acid transporter (LAT; LAT1, LAT2, LAT3, or LAT4) has multiple functions in human biology, including the cellular import of S-nitrosothiols (SNOs), biologically active derivatives of nitric oxide (NO). SNO formation by haemoglobin within red blood cells (RBC) has been studied, but the conduit whereby a SNO leaves the RBC remains unidentified. Here we hypothesised that SNO export by RBCs may also depend on LAT activity, and investigated the role of RBC LAT in modulating SNO-sensitive RBC-endothelial cell (EC) adhesion. We used multiple pharmacologic inhibitors of LAT in vitro and in vivo to test the role of LAT in SNO export from RBCs and in thereby modulating RBC-EC adhesion. Inhibition of human RBC LAT by type-1-specific or nonspecific LAT antagonists increased RBC-endothelial adhesivity in vitro, and LAT inhibitors tended to increase post-transfusion RBC sequestration in the lung and decreased oxygenation in vivo. A LAT1-specific inhibitor attenuated SNO export from RBCs, and we demonstrated LAT1 in RBC membranes and LAT1 mRNA in reticulocytes. The proadhesive effects of inhibiting LAT1 could be overcome by supplemental L-CSNO (S-nitroso-L-cysteine), but not D-CSNO or L-Cys, and suggest a basal anti-adhesive role for stereospecific intercellular SNO transport. This study reveals for the first time a novel role of LAT1 in the export of SNOs from RBCs to prevent their adhesion to ECs. The findings have implications for the mechanisms of intercellular SNO signalling, and for thrombosis, sickle cell disease, and post-storage RBC transfusion, when RBC adhesivity is increased.

scholarly journals Characterization of the amino acid response element within the human sodium-coupled neutral amino acid transporter 2 (SNAT2) System A transporter gene

2006 ◽  
Vol 395 (3) ◽  
pp. 517-527 ◽  
Author(s):  
Stela S. Palii ◽  
Michelle M. Thiaville ◽  
Yuan-Xiang Pan ◽  
Can Zhong ◽  
Michael S. Kilberg
Keyword(s):  
Amino Acid ◽  
Rna Polymerase Ii ◽  
Mammalian Cells ◽  
Amino Acid Transporter ◽  
Neutral Amino Acid ◽  
System A ◽  
Neutral Amino Acid Transporter ◽  
Acid Transporter ◽  
Amino Acid Response

The neutral amino acid transport activity, System A, is enhanced by amino acid limitation of mammalian cells. Of the three gene products that encode System A activity, the one that exhibits this regulation is SNAT2 (sodium-coupled neutral amino acid transporter 2). Fibroblasts that are deficient in the amino acid response pathway exhibited little or no induction of SNAT2 mRNA. Synthesis of SNAT2 mRNA increased within 1–2 h after amino acid removal from HepG2 human hepatoma cells. The amino acid responsive SNAT2 genomic element that mediates the regulation has been localized to the first intron. Increased binding of selected members of the ATF (activating transcription factor) and C/EBP (CCAAT/enhancer-binding protein) families to the intronic enhancer was established both in vitro and in vivo. In contrast, there was no significant association of these factors with the SNAT2 promoter. Expression of exogenous individual ATF and C/EBP proteins documented that specific family members are associated with either activation or repression of SNAT2 transcription. Chromatin immunoprecipitation analysis established in vivo that amino acid deprivation led to increased RNA polymerase II recruitment to the SNAT2 promoter.

scholarly journals Deletion of P2X7 Receptor Decreases Basal Glutathione Level by Changing Glutamate-Glutamine Cycle and Neutral Amino Acid Transporters

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 995 ◽  
Author(s):  
Hana Park ◽  
Ji-Eun Kim
Keyword(s):  
Amino Acid ◽  
P2x7 Receptor ◽  
Neuronal Excitability ◽  
Defense Mechanism ◽  
Glutamate Uptake ◽  
Neutral Amino Acid ◽  
Amino Acid Transporters ◽  
Glutamine Synthase ◽  
Expression Activity ◽  
P2x7r Activation

Glutathione (GSH) is an endogenous tripeptide antioxidant that consists of glutamate-cysteine-glycine. GSH content is limited by the availability of glutamate and cysteine. Furthermore, glutamine is involved in the regulation of GSH synthesis via the glutamate–glutamine cycle. P2X7 receptor (P2X7R) is one of the cation-permeable ATP ligand-gated ion channels, which is involved in neuronal excitability, neuroinflammation and astroglial functions. In addition, P2X7R activation decreases glutamate uptake and glutamine synthase (GS) expression/activity. In the present study, we found that P2X7R deletion decreased the basal GSH level without altering GSH synthetic enzyme expressions in the mouse hippocampus. P2X7R deletion also increased expressions of GS and ASCT2 (a glutamine:cysteine exchanger), but diminished the efficacy of N-acetylcysteine (NAC, a GSH precursor) in the GSH level. SIN-1 (500 μM, a generator nitric oxide, superoxide and peroxynitrite), which facilitates the cystine–cysteine shuttle mediated by xCT (a glutamate/cystein:cystine/NAC antiporter), did not affect basal GSH concentration in WT and P2X7R knockout (KO) mice. However, SIN-1 effectively reduced the efficacy of NAC in GSH synthesis in WT mice, but not in P2X7R KO mice. Therefore, our findings indicate that P2X7R may be involved in the maintenance of basal GSH levels by regulating the glutamate–glutamine cycle and neutral amino acid transports under physiological conditions, which may be the defense mechanism against oxidative stress during P2X7R activation.

scholarly journals L-Type Amino Acid Transporters LAT1 and LAT4 in Cancer: Uptake of 3-O-Methyl-6- 18F-Fluoro-L-Dopa in Human Adenocarcinoma and Squamous Cell Carcinoma In Vitro and In Vivo

2007 ◽  
Vol 48 (12) ◽  
pp. 2063-2071 ◽  
Author(s):  
C. Haase ◽  
R. Bergmann ◽  
F. Fuechtner ◽  
A. Hoepping ◽  
J. Pietzsch
Keyword(s):  
Squamous Cell Carcinoma ◽  
Amino Acid ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Amino Acid Transporters

scholarly journals Epithelial neutral amino acid transporters

2013 ◽  
Vol 22 (5) ◽  
pp. 539-544 ◽  
Author(s):  
Stefan Bröer
Keyword(s):  
Amino Acid ◽  
Neutral Amino Acid ◽  
Amino Acid Transporters

scholarly journals CD98hc (SLC3A2) regulation of skin homeostasis wanes with age

2013 ◽  
Vol 210 (1) ◽  
pp. 173-190 ◽  
Author(s):  
Etienne Boulter ◽  
Soline Estrach ◽  
Aurélia Errante ◽  
Catherine Pons ◽  
Laurence Cailleteau ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Amino Acid ◽  
Molecular Mechanisms ◽  
Skin Aging ◽  
Amino Acid Transporters ◽  
Appreciable Effect ◽  
Nucleotide Exchange ◽  
Aged Skin

Skin aging is linked to reduced epidermal proliferation and general extracellular matrix atrophy. This involves factors such as the cell adhesion receptors integrins and amino acid transporters. CD98hc (SLC3A2), a heterodimeric amino acid transporter, modulates integrin signaling in vitro. We unravel CD98hc functions in vivo in skin. We report that CD98hc invalidation has no appreciable effect on cell adhesion, clearly showing that CD98hc disruption phenocopies neither CD98hc knockdown in cultured keratinocytes nor epidermal β1 integrin loss in vivo. Instead, we show that CD98hc deletion in murine epidermis results in improper skin homeostasis and epidermal wound healing. These defects resemble aged skin alterations and correlate with reduction of CD98hc expression observed in elderly mice. We also demonstrate that CD98hc absence in vivo induces defects as early as integrin-dependent Src activation. We decipher the molecular mechanisms involved in vivo by revealing a crucial role of the CD98hc/integrins/Rho guanine nucleotide exchange factor (GEF) leukemia-associated RhoGEF (LARG)/RhoA pathway in skin homeostasis. Finally, we demonstrate that the deregulation of RhoA activation in the absence of CD98hc is also a result of impaired CD98hc-dependent amino acid transports.

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