scholarly journals Role of cationic amino acid transporters in the regulation of nitric oxide synthesis in vascular cells

2003 ◽  
pp. 12-15 ◽  
Author(s):  
Anwar Baydoun ◽  
Giovanni Mann
Keyword(s):  
Nitric Oxide ◽  
Amino Acid ◽  
Amino Acid Transporters ◽  
Vascular Cells ◽  
Nitric Oxide Synthesis ◽  
Cationic Amino Acid

scholarly journals Nitric oxide can acutely modulate its biosynthesis through a negative feedback mechanism on l-arginine transport in cardiac myocytes

2010 ◽  
Vol 299 (2) ◽  
pp. C230-C239 ◽  
Author(s):  
Jiaguo Zhou ◽  
David D. Kim ◽  
R. Daniel Peluffo
Keyword(s):  
Nitric Oxide ◽  
Amino Acid ◽  
Cardiac Myocytes ◽  
Amino Acid Transporters ◽  
No Production ◽  
Cardiac Muscle Cells ◽  
No Donor ◽  
Rat Cardiomyocytes ◽  
Cationic Amino Acid ◽  
Intervention Point

Nitric oxide (NO) plays a central role as a cellular signaling molecule in health and disease. In the heart, NO decreases the rate of spontaneous beating and the velocity and extent of shortening and accelerates the velocity of relengthening. Since the cationic amino acid l-arginine (l-Arg) is the substrate for NO production by NO synthases (NOS), we tested whether the transporters that mediate l-Arg import in cardiac muscle cells represent an intervention point in the regulation of NO synthesis. Electrical currents activated by l-Arg with low apparent affinity in whole cell voltage-clamped rat cardiomyocytes were found to be rapidly and reversibly inhibited by NO donors. Radiotracer uptake studies performed on cardiac sarcolemmal vesicles revealed the presence of high-affinity/low-capacity and low-affinity/high-capacity components of cationic amino acid transport that were inhibited by the NO donor S-nitroso- N-acetyl-dl-penicillamine. NO inhibited uptake in a noncompetitive manner with Ki values of 275 and 827 nM for the high- and low-affinity component, respectively. Fluorescence spectroscopy experiments showed that millimolar concentrations of l-Arg initially promoted and then inhibited the release of endogenous NO in cardiomyocytes. Likewise, l-Arg currents measured in cardiac myocytes voltage clamped in the presence of 460 nM free intracellular Ca2+, a condition in which a Ca-CaM complex should activate endogenous NO production, showed fast activation followed by inhibition of l-Arg transport. The NOS inhibitor N-nitro-l-arginine methyl ester, but not blockers of downstream reactions, specifically removed this inhibitory component. These results demonstrate that NO acutely regulates its own biosynthesis by modulating the availability of l-Arg via cationic amino acid transporters.

scholarly journals Membrane topology of the Escherichia coli γ-aminobutyrate transporter: implications on the topography and mechanism of prokaryotic and eukaryotic transporters from the APC superfamily

1998 ◽  
Vol 336 (1) ◽  
pp. 69-76 ◽  
Author(s):  
Liaoyuan A. HU ◽  
Steven C. KING
Keyword(s):  
Escherichia Coli ◽  
Amino Acid ◽  
Membrane Topology ◽  
Amino Acid Transporters ◽  
Cationic Amino Acid ◽  
Transmembrane Segments ◽  
Bacteria And Fungi ◽  
Significant Region ◽  
Hydropathy Analysis

The Escherichia coli γ-aminobutyric acid permease (GabP) is a plasma membrane protein from the amine–polyamine–choline (APC) superfamily. On the basis of hydropathy analysis, transporters from this family are thought to contain 12, 13 or 14 transmembrane domains. We have experimentally analysed the topography of GabP by using the cytoplasmically active LacZ (β-galactosidase) and the periplasmically active PhoA (alkaline phosphatase) as complementary topological sensors. The enzymic activities of 32 GabP–LacZ hybrids and 43 GabP–PhoA hybrids provide mutually reinforcing lines of evidence that the E. coliGabP contains 12 transmembrane segments that traverse the membrane in a zig-zag fashion with both N- and C-termini facing the cytoplasm. Interestingly, the resulting model predicts that the functionally important ‘consensus amphipathic region ’ (CAR) [Hu and King (1998) Biochem. J. 330, 771–776] is at least partly membrane-embedded in many amino acid transporters from bacteria and fungi, in contrast with the apparent situation in mouse cationic amino acid transporters (MCATs), in which this kinetically significant region is thought to be fully cytoplasmic [Sophianopoulou and Diallinas (1995) FEMS Microbiol. Rev. 16, 53–75]. To the extent that conserved domains serve similar functions, the resolution of this topological disparity stands to have family-wide implications on the mechanistic role of the CAR. The consensus transmembrane structure derived from this analysis of GabP provides a foundation for predicting the topological disposition of the CAR and other functionally important domains that are conserved throughout the APC transporter superfamily.

The red blood cell: a new key player in cardiovascular homoeostasis? Focus on the nitric oxide pathway

2014 ◽  
Vol 42 (4) ◽  
pp. 996-1000 ◽  
Author(s):  
Benedetta Porro ◽  
Sonia Eligini ◽  
Isabella Squellerio ◽  
Elena Tremoli ◽  
Viviana Cavalca
Keyword(s):  
Nitric Oxide ◽  
Blood Cells ◽  
Tissue Oxygenation ◽  
Blood Rheology ◽  
Amino Acid Transporters ◽  
Arginine Metabolism ◽  
Cationic Amino Acid ◽  
Physiological Processes ◽  
Oxide Synthase

RBCs (red blood cells) have a fundamental role in the regulation of vascular homoeostasis thanks to the ability of these cells to carry O2 (oxygen) between respiratory surfaces and metabolizing tissues and to release vasodilator compounds, such as ATP and NO (nitric oxide), in response to tissue oxygenation. More recently it has been shown that RBCs are also able to produce NO endogenously as they express a functional NOS (nitric oxide synthase), similar to the endothelial isoform. In addition, RBCs carry important enzymes and molecules involved in L-arginine metabolism, such as arginase, NO synthesis inhibitors and the cationic amino acid transporters. Altogether these findings strongly support the role of these cells as producers, vehicles and scavengers of NO, therefore affecting several physiological processes such as blood rheology and cell adhesion. Consequently, the importance of alterations in the L-arginine/NO metabolic pathway induced by specific conditions, e.g. oxidative stress, in different pathological settings have been investigated. In the present review we discuss the role of RBCs in vascular homoeostasis, focusing our attention on the importance of the NO pathway alterations in cardiovascular diseases and their relationship to major risk factors.

scholarly journals Expression Profile of Cationic Amino Acid Transporters in Rats with Endotoxin-Induced Uveitis

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Yung-Ray Hsu ◽  
Shu-Wen Chang ◽  
Chang-Hao Yang ◽  
Yi-An Lee ◽  
Tzu-Yun Kao
Keyword(s):  
Nitric Oxide ◽  
Amino Acid ◽  
Histopathological Examination ◽  
Raw 264.7 Cells ◽  
Amino Acid Transporters ◽  
Raw 264.7 ◽  
Mobility Shift ◽  
Cationic Amino Acid ◽  
Cat Isoforms

Purpose. The transcellular arginine transportation via cationic amino acid transporter (CAT) is the rate-limiting step in nitric oxide (NO) synthesis, which is crucial in intraocular inflammation. In this study, CAT isoforms and inducible nitric oxide synthase (iNOS) expression was investigated in endotoxin-induced uveitis (EIU).Methods.EIU was induced in Lewis rats by lipopolysaccharide (LPS) injection. In the treatment group, the rats were injected intraperitoneally with the proteasome inhibitor bortezomib before EIU induction. After 24 hours, leukocyte quantification, NO measurement of the aqueous humor, and histopathological examination were evaluated. The expression of CAT isoforms and iNOS was determined by reverse transcription-polymerase chain reaction, western blotting, and immunofluorescence staining. Nuclear factor-kappa B (NF-κB) binding activity was evaluated by electrophoretic mobility shift assay. The mouse macrophage cell line RAW 264.7 was used to validate thein vivofindings.Results. LPS significantly stimulated iNOS, CAT-2A, and CAT-2B mRNA and protein expression but did not affect CAT-1 in EIU rats and RAW 264.7 cells. Bortezomib attenuated inflammation and inhibited iNOS, CAT-2A, and CAT-2B expression through NF-κB inhibition.Conclusions.CAT-2 and iNOS, but not CAT-1, are specifically involved in EIU. NF-κB is essential in the induction of CAT-2 and iNOS in EIU.

scholarly journals Transmembrane signalling mechanisms regulating expression of cationic amino acid transporters and inducible nitric oxide synthase in rat vascular smooth muscle cells

1999 ◽  
Vol 344 (1) ◽  
pp. 265-272 ◽  
Author(s):  
Anwar R. BAYDOUN ◽  
Samantha M. WILEMAN ◽  
Caroline P. D. WHEELER-JONES ◽  
Michael S. MARBER ◽  
Giovanni E. MANN ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Amino Acid ◽  
Nitric Oxide Synthase ◽  
P38 Mapk ◽  
Amino Acid Transporters ◽  
Cationic Amino Acid ◽  
Arginine Transport ◽  
Ifn Γ ◽  
Oxide Synthase

The signalling mechanisms involved in the induction of nitric oxide synthase and L-arginine transport were investigated in bacterial lipopolysaccharide (LPS)- and interferon-γ (IFN-γ)-stimulated rat cultured aortic smooth muscle cells (RASMCs). The expression profile of transcripts for cationic amino acid transporters (CATs) and their regulation by LPS and IFN-γ were also examined. Control RASMCs expressed mRNA for CAT-1, CAT-2A and CAT-2B. Levels of all three transcripts were significantly elevated in activated cells. Stimulated CAT mRNA expression and L-arginine transport occurred independently of protein kinase C (PKC), protein tyrosine kinase (PTK) and p44/42 mitogen-activated kinases (MAPKs), but were inhibited by the p38 MAPK inhibitor SB203580, which at 3 μM caused maximum inhibition of both responses. Induction of NO synthesis was independent of p44/42 MAPK activation and only marginally dependent on PKC, but was attenuated markedly by the PTK inhibitors genistein and herbimycin A. SB203580 differentially regulated inducible NO synthase expression and NO production, potentiating both processes at low micromolar concentrations and inhibiting at concentrations of ⩾ 1 μM. In conclusion, our results suggest that RASMCs constitutively express transcripts for CAT-1, CAT-2A and CAT-2B, and that expression of these transcripts is significantly enhanced by LPS and IFN-γ. Moreover, stimulation of L-arginine transport and induction of NO synthesis by LPS and IFN-γ appear to be under critical regulation by the p38 MAPK, since both processes were significantly modified by SB203580 at concentrations so far shown to have no effect on other signalling pathways. Thus, in RASMCs, the p38 MAPK cascade represents an important signalling mechanism, regulating both enhanced L-arginine transport and induced NO synthesis.

The Role of Large Neutral Amino Acid Transporter (LAT1) in Cancer

2019 ◽  
Vol 19 (11) ◽  
pp. 863-876 ◽  
Author(s):  
Xinjie Lu
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Metabolic Networks ◽  
Amino Acid Transporter ◽  
Amino Acid Transporters ◽  
Large Neutral Amino Acid ◽  
Pharmaceutical Drugs ◽  
Cationic Amino Acid ◽  
Acid Transporter

Background: The solute carrier family 7 (SLC7) can be categorically divided into two subfamilies, the L-type amino acid transporters (LATs) including SLC7A5-13, and SLC7A15, and the cationic amino acid transporters (CATs) including SLC7A1-4 and SLC7A14. Members of the CAT family transport predominantly cationic amino acids by facilitating diffusion with intracellular substrates. LAT1 (also known as SLC7A5), is defined as a heteromeric amino acid transporter (HAT) interacting with the glycoprotein CD98 (SLC3A2) through a conserved disulfide to uptake not only large neutral amino acids, but also several pharmaceutical drugs to cells. Methods: In this review, we provide an overview of the interaction of the structure-function of LAT1 and its essential role in cancer, specifically, its role at the blood-brain barrier (BBB) to facilitate the transport of thyroid hormones, pharmaceuticals (e.g., I-DOPA, gabapentin), and metabolites into the brain. Results: LAT1 expression increases as cancers progress, leading to higher expression levels in highgrade tumors and metastases. In addition, LAT1 plays a crucial role in cancer-associated reprogrammed metabolic networks by supplying tumor cells with essential amino acids. Conclusion: The increasing understanding of the role of LAT1 in cancer has led to an increase in interest surrounding its potential as a drug target for cancer treatment.

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