The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Yoshikatsu Kanai - One of the best experts on this subject based on the ideXlab platform.
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Amino Acid Transporters revisited: New views in health and disease.
Trends in Biochemical Sciences, 2018Co-Authors: Palanivel Kandasamy, Gergely Gyimesi, Yoshikatsu Kanai, Matthias A HedigerAbstract:Amino Acid Transporters (AATs) are membrane-bound transport proteins that mediate transfer of Amino Acids into and out of cells or cellular organelles. AATs have diverse functional roles ranging from neurotransmission to Acid-base balance, intracellular energy metabolism, and anabolic and catabolic reactions. In cancer cells and diabetes, dysregulation of AATs leads to metabolic reprogramming, which changes intracellular Amino Acid levels, contributing to the pathogenesis of cancer, obesity and diabetes. Indeed, the neutral Amino Acid Transporters (NATs) SLC7A5/LAT1 and SLC1A5/ASCT2 are likely involved in several human malignancies. However, a clinical therapy that directly targets AATs has not yet been developed. The purpose of this review is to highlight the structural and functional diversity of AATs, their diverse physiological roles in different tissues and organs, their wide-ranging implications in human diseases and the emerging strategies and tools that will be necessary to target AATs therapeutically.
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Relationship between CD147 and expression of Amino Acid Transporters (LAT1 and ASCT2) in patients with pancreatic cancer
American journal of translational research, 2015Co-Authors: Kyoichi Kaira, Yoshikatsu Kanai, Kazuhisa Arakawa, Kimihiro Shimizu, Noboru Oriuchi, Shushi Nagamori, Tetsunari Oyama, Izumi TakeyoshiAbstract:CD147 functions as an induction of matrix metalloproteinases and tumor angiogenesis, and is highly expressed in various malignant neoplasms. Recently, CD147 is shown to form a complex with Amino Acid Transporters such as L-type Amino Acid transporter (LAT1), system ASC Amino Acid transporter-2 (ASCT2) and 4F2hc as a heavy chain of LAT1. It remains unknown about the existence of these complexes in patients with pancreatic cancer. The aim of this study is to investigate the relationship between CD147 and these Amino Acid Transporters. Ninety-seven patients with pancreatic cancer were evaluated. Tumor sections were stained by immunohistochemistry for LAT1, ASCT2, Ki-67, microvessel density (MVD) determined by CD34, p-AKT, and p-mTOR. CD147 was highly expressed in 23% (22/97) of patients. A high expression of CD147 is significantly associated with N factor, LAT1, ASCT2, Ki-67, VEGF and p-mTOR. A high CD147 expression was identified as a significant prognostic predictor by univariate survival analysis. The coexpression of CD147 and LAT1, and that of CD147 and 4F2hc yielded a significantly worse prognosis than the single expression of LAT1, and that of 4F2hc, respectively. CD147 revealed a significant relationship with the expression level of LAT1 and ASCT2, correlated with tumor proliferation, angiogenesis and mTOR signaling.
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the small slc43 family facilitator system l Amino Acid Transporters and the orphan eeg1
Molecular Aspects of Medicine, 2013Co-Authors: Susanna Bodoy, Yoshikatsu Kanai, Dimitrios Fotiadis, Claudia Stoeger, Manuel PalacinAbstract:The SLC43 family is composed of only three genes coding for the plasma membrane facilitator system l Amino Acid Transporters LAT3 (SLC43A1; TC 2.A.1.44.1) and LAT4 (SLC43A2; TC 2.A.1.44.2), and the orphan protein EEG1 (SLC43A3; TC 2.A.1.44.3). Besides the known mechanism of transport of LAT3 and LAT4, their physiological roles still remain quite obscure. Morphants suggested a role of LAT3 in renal podocyte development in zebrafish. Expression in liver and skeletal muscle, and up-regulation by starvation suggest a role of LAT3 in the flux of branched-chain Amino Acids (BCAAs) from liver and skeletal muscle to the bloodstream. Finally, LAT3 is up-regulated in androgen-dependent cancers, suggesting a role in mTORC1 signaling in this type of tumors. In addition, LAT4 might contribute to the transfer of BCAAs from mother to fetus. Unfortunately, the EEG1 mouse model (EEG1(Y221∗)) described here has not yet offered a clue to the physiological role of this orphan protein.
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The SLC3 and SLC7 families of Amino Acid Transporters.
Molecular aspects of medicine, 2013Co-Authors: Dimitrios Fotiadis, Yoshikatsu Kanai, Manuel PalacinAbstract:Amino Acids are necessary for all living cells and organisms. Specialized Transporters mediate the transfer of Amino Acids across plasma membranes. Malfunction of these proteins can affect whole-body homoeostasis giving raise to diverse human diseases. Here, we review the main features of the SLC3 and SLC7 families of Amino Acid Transporters. The SLC7 family is divided into two subfamilies, the cationic Amino Acid Transporters (CATs), and the L-type Amino Acid Transporters (LATs). The latter are the light or catalytic subunits of the heteromeric Amino Acid Transporters (HATs), which are associated by a disulfide bridge with the heavy subunits 4F2hc or rBAT. These two subunits are glycoproteins and form the SLC3 family. Most CAT subfamily members were functionally characterized and shown to function as facilitated diffusers mediating the entry and efflux of cationic Amino Acids. In certain cells, CATs play an important role in the delivery of L-arginine for the synthesis of nitric oxide. HATs are mostly exchangers with a broad spectrum of substrates and are crucial in renal and intestinal re-absorption and cell redox balance. Furthermore, the role of the HAT 4F2hc/LAT1 in tumor growth and the application of LAT1 inhibitors and PET tracers for reduction of tumor progression and imaging of tumors are discussed. Finally, we describe the link between specific mutations in HATs and the primary inherited AminoAcidurias, cystinuria and lysinuric protein intolerance.
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bch an inhibitor of system l Amino Acid Transporters induces apoptosis in cancer cells
Biological & Pharmaceutical Bulletin, 2008Co-Authors: Chun Sung Kim, Hitoshi Endou, Yoshikatsu Kanai, Seonho Cho, Hong Sung Chun, Sookyoung Lee, Do Kyung KimAbstract:Purpose: L-Type Amino Acid transporter 1 (LAT1) is highly expressed in cancer cells to support their continuous growth and proliferation. We have examined the effect of 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic Acid (BCH), an inhibitor of system L Amino Acid Transporters, and the mechanism by which BCH suppresses cell growth in cancer cells. Methods: The effect of BCH and the mechanism of BCH on cell growth suppression in cancer cells were examined using Amino Acid transport measurement, MTT assay, DNA fragmentation analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and immunoblotting. Results: BCH inhibited L-leucine transport in a concentration-dependent manner, and it inhibited cell growth in a time-dependent manner in KB human oral epidermoid carcinoma cells, Saos2 human osteogenic sarcoma cells and C6 rat glioma cells. The formation of a DNA ladder was observed, and the number of TUNEL-positive cells was increased with BCH treatment. Furthermore, the proteolytic processing of caspase-3 in KB and C6 cells and of caspase-7 in KB, Saos2 and C6 cells was increased by BCH treatment. Conclusion: These results suggest that the inhibition of LAT1 activity by BCH leads to apoptotic cancer cell death by inducing intracellular depletion of neutral Amino Acids necessary for cancer cell growth.
Manuel Palacin - One of the best experts on this subject based on the ideXlab platform.
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the small slc43 family facilitator system l Amino Acid Transporters and the orphan eeg1
Molecular Aspects of Medicine, 2013Co-Authors: Susanna Bodoy, Yoshikatsu Kanai, Dimitrios Fotiadis, Claudia Stoeger, Manuel PalacinAbstract:The SLC43 family is composed of only three genes coding for the plasma membrane facilitator system l Amino Acid Transporters LAT3 (SLC43A1; TC 2.A.1.44.1) and LAT4 (SLC43A2; TC 2.A.1.44.2), and the orphan protein EEG1 (SLC43A3; TC 2.A.1.44.3). Besides the known mechanism of transport of LAT3 and LAT4, their physiological roles still remain quite obscure. Morphants suggested a role of LAT3 in renal podocyte development in zebrafish. Expression in liver and skeletal muscle, and up-regulation by starvation suggest a role of LAT3 in the flux of branched-chain Amino Acids (BCAAs) from liver and skeletal muscle to the bloodstream. Finally, LAT3 is up-regulated in androgen-dependent cancers, suggesting a role in mTORC1 signaling in this type of tumors. In addition, LAT4 might contribute to the transfer of BCAAs from mother to fetus. Unfortunately, the EEG1 mouse model (EEG1(Y221∗)) described here has not yet offered a clue to the physiological role of this orphan protein.
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The SLC3 and SLC7 families of Amino Acid Transporters.
Molecular aspects of medicine, 2013Co-Authors: Dimitrios Fotiadis, Yoshikatsu Kanai, Manuel PalacinAbstract:Amino Acids are necessary for all living cells and organisms. Specialized Transporters mediate the transfer of Amino Acids across plasma membranes. Malfunction of these proteins can affect whole-body homoeostasis giving raise to diverse human diseases. Here, we review the main features of the SLC3 and SLC7 families of Amino Acid Transporters. The SLC7 family is divided into two subfamilies, the cationic Amino Acid Transporters (CATs), and the L-type Amino Acid Transporters (LATs). The latter are the light or catalytic subunits of the heteromeric Amino Acid Transporters (HATs), which are associated by a disulfide bridge with the heavy subunits 4F2hc or rBAT. These two subunits are glycoproteins and form the SLC3 family. Most CAT subfamily members were functionally characterized and shown to function as facilitated diffusers mediating the entry and efflux of cationic Amino Acids. In certain cells, CATs play an important role in the delivery of L-arginine for the synthesis of nitric oxide. HATs are mostly exchangers with a broad spectrum of substrates and are crucial in renal and intestinal re-absorption and cell redox balance. Furthermore, the role of the HAT 4F2hc/LAT1 in tumor growth and the application of LAT1 inhibitors and PET tracers for reduction of tumor progression and imaging of tumors are discussed. Finally, we describe the link between specific mutations in HATs and the primary inherited AminoAcidurias, cystinuria and lysinuric protein intolerance.
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The role of Amino Acid Transporters in inherited and acquired diseases.
The Biochemical journal, 2011Co-Authors: Stefan Broer, Manuel PalacinAbstract:Amino Acids are essential building blocks of all mammalian cells. In addition to their role in protein synthesis, Amino Acids play an important role as energy fuels, precursors for a variety of metabolites and as signalling molecules. Disorders associated with the malfunction of Amino Acid Transporters reflect the variety of roles that they fulfil in human physiology. Mutations of brain Amino Acid Transporters affect neuronal excitability. Mutations of renal and intestinal Amino Acid Transporters affect whole-body homoeostasis, resulting in malabsorption and renal problems. Amino Acid Transporters that are integral parts of metabolic pathways reduce the function of these pathways. Finally, Amino Acid uptake is essential for cell growth, thereby explaining their role in tumour progression. The present review summarizes the involvement of Amino Acid Transporters in these roles as illustrated by diseases resulting from transporter malfunction.
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The genetics of heteromeric Amino Acid Transporters.
Physiology (Bethesda Md.), 2005Co-Authors: Manuel Palacin, Josep Chillaron, Virginia Nunes, Mariona Font-llitjós, Maite Jiménez-vidal, Joana Fort, Emma Gasol, Marta Pineda, Lídia Feliubadaló, Antonio ZorzanoAbstract:Heteromeric Amino Acid Transporters (HATs) are composed of a heavy (SLC3 family) and a light (SLC7 family) subunit. Mutations in system b0,+ (rBAT-b0,+AT) and in system y+L (4F2hc-y+LAT1) cause the...
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The ancillary proteins of HATs: SLC3 family of Amino Acid Transporters
Pflügers Archiv, 2004Co-Authors: Manuel Palacin, Yoshikatsu KanaiAbstract:The heteromeric Amino Acid Transporters (HATs) are composed of a light and a heavy subunit linked by a disulfide bridge. The heavy subunits are the SLC3 members (rBAT and 4F2hc), whereas the light subunits are members of the SLC7 family of Amino Acid Transporters. SLC3 proteins are type II membrane glycoproteins (i.e., one single transmembrane domain and the C-terminus located outside the cell) with a bulky extracellular domain that shows homology with α-glucosidases. rBAT heterodimerizes with b^0,+AT (SLC7A9) constituting the Amino Acid transport b^0,+, the main system responsible for the apical reabsorption of cystine in kidney. The defect in this system causes cystinuria, the most common primary inherited AminoAciduria. 4F2hc subserves various Amino Acid transport systems by dimerization with different SLC7 proteins. The main role of SLC3 proteins is to help routing of the holotransporter to the plasma membrane. A working model for the biogenesis of HATs based on recent data on the rBAT/b^0,+AT heterodimeric complex is presented. 4F2hc is a multifunctional protein, and in addition to its role in Amino Acid transport, it may be involved in other cellular functions. Studies on two SLC7 members (Asc-2 and AGT1) demonstrate heterodimerization with unknown heavy subunits.
Stefan Broer - One of the best experts on this subject based on the ideXlab platform.
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cationic Amino Acid Transporters play key roles in the survival and transmission of apicomplexan parasites
Nature Communications, 2017Co-Authors: Esther Rajendran, Stefan Broer, Sanduni V Hapuarachchi, Catherine M Miller, Stephen J Fairweather, Yeping Cai, Nicholas C Smith, Ian A Cockburn, Kiaran Kirk, Giel G Van DoorenAbstract:Apicomplexans are obligate intracellular parasites that scavenge essential nutrients from their hosts via transporter proteins on their plasma membrane. The identities of the Transporters that mediate Amino Acid uptake into apicomplexans are unknown. Here we demonstrate that members of an apicomplexan-specific protein family-the Novel Putative Transporters (NPTs)-play key roles in the uptake of cationic Amino Acids. We show that an NPT from Toxoplasma gondii (TgNPT1) is a selective arginine transporter that is essential for parasite survival and virulence. We also demonstrate that a homologue of TgNPT1 from the malaria parasite Plasmodium berghei (PbNPT1), shown previously to be essential for the sexual gametocyte stage of the parasite, is a cationic Amino Acid transporter. This reveals a role for cationic Amino Acid scavenging in gametocyte biology. Our study demonstrates a critical role for Amino Acid Transporters in the survival, virulence and life cycle progression of these parasites.
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molecular basis for the interaction of the mammalian Amino Acid Transporters b0at1 and b0at3 with their ancillary protein collectrin
Journal of Biological Chemistry, 2015Co-Authors: Stephen J Fairweather, Qi Cheng, Angelika Broer, Nandhitha Subramanian, Emrah Tumer, Dieter Schmoll, Megan L Omara, Stefan BroerAbstract:Many solute carrier 6 (SLC6) family Transporters require ancillary subunits to modify their expression and activity. The main apical membrane neutral Amino Acid Transporters in mouse intestine and kidney, B0AT1 and B0AT3, require the ancillary protein collectrin or ACE2 for plasma membrane expression. Expression and activity of SLC6 neurotransmitter Transporters are modulated by interaction with syntaxin 1A. Utilizing monocarboxylate-B0AT1/3 fusion constructs, we discovered that collectrin is also necessary for B0AT1 and B0AT3 catalytic function. Syntaxin 1A and syntaxin 3 inhibit the membrane expression of B0AT1 by competing with collectrin for access. A mutagenesis screening approach identified residues on trans-membrane domains 1α, 5, and 7 on one face of B0AT3 as a key region involved in interaction with collectrin. Mutant analysis established residues that were involved in collectrin-dependent functions as follows: plasma membrane expression of B0AT3, catalytic activation, or both. These results identify a potential binding site for collectrin and other SLC6 ancillary proteins.
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The role of Amino Acid Transporters in inherited and acquired diseases.
The Biochemical journal, 2011Co-Authors: Stefan Broer, Manuel PalacinAbstract:Amino Acids are essential building blocks of all mammalian cells. In addition to their role in protein synthesis, Amino Acids play an important role as energy fuels, precursors for a variety of metabolites and as signalling molecules. Disorders associated with the malfunction of Amino Acid Transporters reflect the variety of roles that they fulfil in human physiology. Mutations of brain Amino Acid Transporters affect neuronal excitability. Mutations of renal and intestinal Amino Acid Transporters affect whole-body homoeostasis, resulting in malabsorption and renal problems. Amino Acid Transporters that are integral parts of metabolic pathways reduce the function of these pathways. Finally, Amino Acid uptake is essential for cell growth, thereby explaining their role in tumour progression. The present review summarizes the involvement of Amino Acid Transporters in these roles as illustrated by diseases resulting from transporter malfunction.
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The SLC6 orphans are forming a family of Amino Acid Transporters.
Neurochemistry international, 2006Co-Authors: Stefan BroerAbstract:Transporters in the human genome are grouped in solute carrier families (SLC). The SLC6 family is one of the biggest transporter families in the human genome comprising 20 members. It is usually referred to as the neurotransmitter transporter family because its founding members encode Transporters for the neurotransmitters GABA, noradrenaline, serotonin and dopamine. The family also includes a number of 'orphan' Transporters, the function of which has remained elusive until recently. Identification of the broadly specific neutral Amino Acid transporter SLC6A19 (also called B(0)AT1) suggested that all orphan Transporters may in fact be Amino Acid Transporters. This was subsequently confirmed by the identification of SLC6A20 as the long-sought IMINO system, a proline transporter found in kidney, intestine and brain. Very recently, SLC6A15 was identified as the neutral Amino Acid transporter B(0)AT2. All Amino Acid Transporters appear to cotransport only 1Na(+) together with the Amino Acid substrate. Both, B(0)AT1 and B(0)AT2 are chloride independent, whereas IMINO is chloride dependent. The Amino Acid Transporters of the SLC6 family are functionally and sequence related to the recently crystallized leucine transporter from Aquifex aeolicus. The structure elegantly explains many of the mechanistic features of the SLC6 Amino Acid Transporters.
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Function and structure of heterodimeric Amino Acid Transporters.
American journal of physiology. Cell physiology, 2001Co-Authors: Carsten A. Wagner, Florian Lang, Stefan BroerAbstract:Heterodimeric Amino Acid Transporters are comprised of two subunits, a polytopic membrane protein (light chain) and an associated type II membrane protein (heavy chain). The heavy chain rbAT (relat...
Hitoshi Endou - One of the best experts on this subject based on the ideXlab platform.
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bch an inhibitor of system l Amino Acid Transporters induces apoptosis in cancer cells
Biological & Pharmaceutical Bulletin, 2008Co-Authors: Chun Sung Kim, Hitoshi Endou, Yoshikatsu Kanai, Seonho Cho, Hong Sung Chun, Sookyoung Lee, Do Kyung KimAbstract:Purpose: L-Type Amino Acid transporter 1 (LAT1) is highly expressed in cancer cells to support their continuous growth and proliferation. We have examined the effect of 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic Acid (BCH), an inhibitor of system L Amino Acid Transporters, and the mechanism by which BCH suppresses cell growth in cancer cells. Methods: The effect of BCH and the mechanism of BCH on cell growth suppression in cancer cells were examined using Amino Acid transport measurement, MTT assay, DNA fragmentation analysis, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and immunoblotting. Results: BCH inhibited L-leucine transport in a concentration-dependent manner, and it inhibited cell growth in a time-dependent manner in KB human oral epidermoid carcinoma cells, Saos2 human osteogenic sarcoma cells and C6 rat glioma cells. The formation of a DNA ladder was observed, and the number of TUNEL-positive cells was increased with BCH treatment. Furthermore, the proteolytic processing of caspase-3 in KB and C6 cells and of caspase-7 in KB, Saos2 and C6 cells was increased by BCH treatment. Conclusion: These results suggest that the inhibition of LAT1 activity by BCH leads to apoptotic cancer cell death by inducing intracellular depletion of neutral Amino Acids necessary for cancer cell growth.
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cats and hats the slc7 family of Amino Acid Transporters
Pflügers Archiv: European Journal of Physiology, 2004Co-Authors: Francois Verrey, Hitoshi Endou, Ellen I Closs, Carste A Wagne, Manuel Palaci, Yoshikatsu KanaiAbstract:The SLC7 family is divided into two subgroups, the cationic Amino Acid Transporters (the CAT family, SLC7A1–4) and the glycoprotein-associated Amino Acid Transporters (the gpaAT family, SLC7A5–11), also called light chains or catalytic chains of the hetero(di)meric Amino Acid Transporters (HAT). The associated glycoproteins (heavy chains) 4F2hc (CD98) or rBAT (D2, NBAT) form the SLC3 family. Members of the CAT family transport essentially cationic Amino Acids by facilitated diffusion with differential trans-stimulation by intracellular substrates. In some cells, they may regulate the rate of NO synthesis by controlling the uptake of l-arginine as the substrate for nitric oxide synthase (NOS). The heterodimeric Amino Acid Transporters are, in contrast, quite diverse in terms of substrate selectivity and function (mostly) as obligatory exchangers. Their selectivity ranges from large neutral Amino Acids (system L) to small neutral Amino Acids (ala, ser, cys-preferring, system asc), negatively charged Amino Acid (system xc−) and cationic Amino Acids plus neutral Amino Acids (system y+L and b0,+-like). Cotransport of Na+ is observed only for the y+L Transporters when they carry neutral Amino Acids. Mutations in b0,+-like and y+L Transporters lead to the hereditary diseases cystinuria and lysinuric protein intolerance (LPI), respectively.
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functional properties of multispecific Amino Acid Transporters and their implications to transporter mediated toxicity
Journal of Toxicological Sciences, 2003Co-Authors: Yoshikatsu Kanai, Hitoshi EndouAbstract:The absorption, distribution and excretion of most of xenobiotics, drugs, environmental toxins and their metabolites are mediated by membrane Transporters. Recent advances in the transporter molecular biology have made it possible to investigate the mechanisms of transport of those exogenous compounds and their transporter-mediated toxicity at the molecular level. Exogenous compounds including drugs and toxic substances occurring in the environment pass through the Transporters with broad substrate selectivity, namely "multispecific" Transporters, taking advantage of the multispecific nature to exert their toxic effects. The remarkable examples of such transporter-mediated toxicity are 1-methyl-4-phenyl-2,3-dihydropyridinium (MPP+)-neurotoxicity mediated by dopamine Transporters, cephaloridine-nephrotoxicity mediated by organic anion Transporters and methylmercury-toxicity mediated by system L Amino Acid Transporters. The molecular identification of system L transporter LAT1 (L-type Amino Acid transporter 1) has lead to the understanding of the mechanisms of their multispecific substrate recognition and revealed their localization at the blood-brain barrier and placental barrier. LAT1 relies on the hydrophobic interaction between substrate Amino Acid side chains and the substrate binding site, so that many variations are possible for the substrate Amino Acid side chains, which is the basis of the broad substrate selectivity. System L Transporters, thus, function as a path for the membrane permeation of drugs and toxic compounds occurring in the environment with Amino Acid-related structures. Beside methylmercury-cysteine conjugate, Amino Acid-related neurotoxins such as β-N-methylAmino-L-alanine, S-(1,2-dichlorovinyl)-L-cysteine and 3-hydroxykynurenine are proposed to pass through system L Transporters to exert their toxicity. Because the presence of such Transporters is crucial for the manifestation of the organ toxicity, the inhibition of the Transporters would be expected to be beneficial to prevent the disorders caused by the transporter-mediated toxicity.
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Heterodimeric Amino Acid Transporters: molecular biology and pathological and pharmacological relevance.
Current drug metabolism, 2001Co-Authors: Yoshikatsu Kanai, Hitoshi EndouAbstract:In the last decade, a lot of Amino Acid Transporters were identified by molecular cloning and assigned to the classically characterized Amino Acid transport systems. Among them, ones which belong to the heterodimeric Amino Acid transporter family are unique because of their broad substrate selectivity and their pathological implications as well as their structural features. The heterodimeric Amino Acid transporter family is a subfamily of SLC7 solute transporter family which includes 14-transmembrane cationic Amino Acid Transporters as well as 12-transmembrane heterodimeric Amino Acid Transporters. The members of heterodimeric Amino Acid transporter family are linked via a disulfide bond to single membrane spanning type II membrane glycoproteins such as 4F2hc (4F2 heavy chain) and rBAT (related to b(0,+)-Amino Acid transporter). Six members are associated with 4F2hc and one is linked to rBAT. The neutral Amino Acid transporter of this family seems to rely on the hydrophobic interactions for their substrate recognition which can explain their broad substrate selectivity. Because of this characteristic, they can permeate Amino-Acid-related drugs and contribute to the pharmacokinetics of these drugs. A neutral Amino Acid transporter LAT1 (L-type Amino Acid transporter 1) has actually been shown to be present at the blood-brain-barrier. Because the members of the heterodimeric Amino Acid transporter family exhibit variety of substrate selectivity, it is proposed that this family members have been diverged from the prototype neutral Amino Acid transporter such as LAT1 by acquiring the mechanisms for the recognition of electric charges on the substrate Amino Acid side chains. The dysfunction or hyperfunction of the members of the heterodimeric Amino Acid transporter family are involved in some diseases and pathologic conditions. The genetic defects of the renal and intestinal Transporters BAT1/b(0,+) AT (b(0,+)-type Amino Acid transporter 1/b(0,+)-type Amino Acid transporter) and y+ LAT1 (y+ L-type Amino Acid transporter 1) result in the Amino Aciduria with sever clinical symptoms such as cystinuria and lysinuric protein intolerance, respectively. LAT1 is proposed to be involved in the progression of malignant tumor. xCT (x- C-type transporter) functions to protect cells against oxidative stress, while its over-function may be damaging neurons leading to the exacerbation of brain damage after, brain ischemia. Therefore, these Transporters would be candidates for therapeutic targets based on new strategies. Through the interaction with the associating proteins, the Transporters of this family would be endowed with more possibility to be regulated via intracellular and extracellular signalling pathways, which is critical to tune the transporter functions to meet the metabolic requirements of cells.
Fuller W Bazer - One of the best experts on this subject based on the ideXlab platform.
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Amino Acid Transporters in t cell activation and differentiation
Cell Death and Disease, 2017Co-Authors: Wenkai Ren, Fuller W Bazer, Jie Yin, Gang Liu, Bie Tan, Yuanyi Peng, Yulong YinAbstract:T-cell-mediated immune responses aim to protect mammals against cancers and infections, and are also involved in the pathogenesis of various inflammatory or autoimmune diseases. Cellular uptake and the utilization of nutrients is closely related to the T-cell fate decision and function. Research in this area has yielded surprising findings in the importance of Amino-Acid Transporters for T-cell development, homeostasis, activation, differentiation and memory. In this review, we present current information on Amino-Acid Transporters, such as LAT1 (l-leucine transporter), ASCT2 (l-glutamine transporter) and GAT-1 (γ-Aminobutyric Acid transporter-1), which are critically important for mediating peripheral naive T-cell homeostasis, activation and differentiation, especially for Th1 and Th17 cells, and even memory T cells. Mechanically, the influence of Amino-Acid Transporters on T-cell fate decision may largely depend on the mechanistic target of rapamycin complex 1 (mTORC1) signaling. These discoveries remarkably demonstrate the role of Amino-Acid Transporters in T-cell fate determination, and strongly indicate that manipulation of the Amino-Acid transporter-mTORC1 axis could ameliorate many inflammatory or autoimmune diseases associated with T-cell-based immune responses.
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select nutrients in the ovine uterine lumen iv expression of neutral and Acidic Amino Acid Transporters in ovine uteri and peri implantation conceptuses
Biology of Reproduction, 2009Co-Authors: Haijun Gao, Gregory A. Johnson, Thomas E Spencer, Fuller W BazerAbstract:The availability of specific neutral and Acidic Amino Acids in the uterine lumen of ewes increased significantly during the peri-implantation period, but mechanisms for their transport into the uterine lumen and uptake by conceptuses are not established in any species. In this study, effects of pregnancy, progesterone (P4), and interferon tau (IFNT) on expression of neutral and Acidic Amino Acid Transporters in uteri of cyclic and pregnant ewes and conceptuses were studied. SLC1A2, SLC1A3, SLC3A1, SLC6A14, SLC6A19, SLC7A6, SLC38A3, and SLC38A6 mRNAs were only weakly expressed in the ovine endometrium. However, SLC1A4, SLC1A5, SLC7A8, and SLC43A2 mRNAs were detectable in uterine luminal epithelia (LE), superficial glandular epithelia (sGE), and/or glandular epithelia (GE). SLC1A1 and SLC7A5 mRNAs were most abundant in LE/sGE and GE. SLC1A3 and SLC38A4 mRNAs were most abundant in uterine stroma. SLC38A6 mRNA was detected only in cells with a stromal distribution suggesting immune lineage. SLC1A5 mRNA was expressed primarily in LE/sGE and stromal cells, and it was more abundant in uteri of pregnant ewes (day x status interaction; P < 0.05). Furthermore, P4 induced and IFNT further stimulated SLC1A5 expression in LE/sGE. Endometrial SLC1A1, SLC7A5, and SLC43A2 mRNAs demonstrated both temporal and cellSLC-specific changes. Several mRNAs were detectable in trophectoderm (SLC6A19, SLC7A5, SLC7A6, and SLC43A2), while others were more abundant in endoderm (SLC1A4, SLC1A5, SLC6A19, SLC7A5, SLC7A6, SLC7A8, and SLC43A2) of conceptuses. These results document coordinate changes in expression of Transporters that are likely responsible for increases in amounts of neutral and Acidic Amino Acids in the uterine lumen to support conceptus growth, development, and survival.
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select nutrients in the ovine uterine lumen iii cationic Amino Acid Transporters in the ovine uterus and peri implantation conceptuses
Biology of Reproduction, 2009Co-Authors: Haijun Gao, Gregory A. Johnson, Thomas E Spencer, Fuller W BazerAbstract:Arginine is an essential Amino Acid for conceptus (embryo/fetus and trophoblast/placenta) growth and development; however, the mechanisms for arginine transport into the uterine lumen and uptake by conceptuses are largely unknown. In this study, expression of System y(+) (SLC7A1, SLC7A2, and SLC7A3) cationic Amino Acid Transporters in uteri of cyclic and pregnant ewes and conceptuses was studied, and effects of pregnancy, progesterone (P4), and interferon tau (IFNT) on their expression were investigated. SLC7A1 mRNA was most abundant in endometrial luminal (LE) and superficial glandular (sGE) epithelia on Day 16 of the estrous cycle and on Days 16-20 of pregnancy, whereas SLC7A2 mRNA was most abundant in LE and mid to deep glandular (GE) epithelia on Days 14-20 of gestation. Expression of SLC7A1 and SLC7A2 was enhanced in pregnant ewes in a cell-specific manner, but abundance of SLC7A3 was not affected by day of the estrous cycle or by pregnancy status. SLC7A1, SLC7A2, and SLC7A3 mRNAs were expressed in trophectoderm and endoderm of conceptuses. In ovariectomized ewes, short-term treatment of ewes with P4 and IFNT did not affect endometrial SLC7A1 mRNA, while long-term treatment with P4 stimulated SLC7A1 in LE and GE, and IFNT tended to increase SLC7A1 abundance in LE. SLC7A2 mRNA abundance increased 4.1-fold in response to short-term P4 treatment and an additional 1.7-fold by IFNT primarily in endometrial LE/sGE, and these effects were ablated by a P4 receptor antagonist. These results indicate that coordinate changes in SLC7A1, SLC7A2, and SLC7A3 expression in uterine endometria and conceptuses are likely important in transport of arginine that is critical to conceptus growth, development, and survival.