Obligatory Amino Acid Exchange via Systems bo,+-like and y+L-like

Chillarón, Josep; Estévez, Raúl; Mora, Conchi; Wagner, Carsten A.; Suessbrich, Hartmut; Läng, Florian; Gelpí, Josep Lluís; Testar, Xavier; Büsch, Andreas; Zorzano, António; Palacı́n, Manuel

doi:10.1074/jbc.271.30.17761

Cited by 162 publications

(52 citation statements)

References 48 publications

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“…This was most noticeable in exit experiments, which demonstrated Na + -dependent, 4F2hc-induced trans-stimulation of lysine efflux by extracellular leucine. Similar findings have been reported recently for human 4F2hc [63] and suggest that 4F2hc and its associated protein(s) function as electroneutral tertiary active amino acid transport systems with obligatory exchange characteristics. Cationic heteroexchange of amino acid with (Na + plus zwitterionic amino acid) provides a potential mechanism to allow the exit of cationic amino acids across intestinal, renal and placental basal membranes against an outside-positive membrane potential, and is consistent with the long-standing observation that efflux of cationic amino acids across the enterocyte basolateral membrane is stimulated by vascular leucine [55][56][57][58].…”

Section: Discussionsupporting

confidence: 73%

Cloning and functional expression of a cDNA from rat jejunal epithelium encoding a protein (4F2hc) with system y+L amino acid transport activity

Yao

Muzyka

Elliott

et al. 1998

Biochemical Journal

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Two different protein families, designated CAT (cationic amino acid transporter) and BAT (broad-specificity amino acid transporter) mediate the plasma membrane transport of cationic amino acids in animal cells. CAT transporters have 12-14 transmembrane domains and are selective for cationic amino acids. BAT proteins, in contrast, have one to four transmembrane domains and induce the transport of both cationic and zwitterionic amino acids when expressed in Xenopus oocytes. Mutations in the human BAT gene cause type I cystinuria, a disease affecting the ability of intestinal and renal brush border membranes to transport cationic amino acids and cystine. We have used functional expression cloning in oocytes to isolate a BAT-related cDNA from rat jejunal epithelium. The cDNA encodes the rat 4F2 heavy chain (4F2hc) cell-surface antigen, a 527-residue (60 kDa) protein that is 26% identical in amino acid sequence with rat renal BAT (also known as NBAT/D2). Expression of rat jejunal 4F2hc in oocytes induced the lysine-inhibitable Na+-dependent influx of leucine and the leucine-inhibitable Na+-independent influx of lysine. Lysine efflux was stimulated by extracellular (Na+ plus leucine). These characteristics identify the expressed amino acid transport activity as system y+L, a transporter that has been implicated in basal membrane transport of cationic amino acids in intestine, kidney and placenta.

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Section: Discussionsupporting

confidence: 73%

Cloning and functional expression of a cDNA from rat jejunal epithelium encoding a protein (4F2hc) with system y+L amino acid transport activity

Yao

Muzyka

Elliott

et al. 1998

Biochemical Journal

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“…System L-and y ϩ L-like transport activity expressed in oocytes seem to show an obligatory exchange, although the molar ratio of exchange is not determined (15,16,20). System L and y ϩ L naturally expressed in cells show marked transstimulation (1,21), that is, the substrate amino acids in one side of the membrane stimulate the exodus of the substrate amino acids from the opposite side of the membrane.…”

Section: Discussionmentioning

confidence: 99%

Cloning and Expression of a Plasma Membrane Cystine/Glutamate Exchange Transporter Composed of Two Distinct Proteins

Sato

Tamba

Ishii

et al. 1999

Journal of Biological Chemistry

933

751

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Transport system x c؊ found in plasma membrane of cultured mammalian cells is an exchange agency for anionic amino acids with high specificity for anionic form of cystine and glutamate. We have isolated cDNA encoding the transporter for system x c Ϫ from mouse activated macrophages by expression in Xenopus oocytes. The expression of system x c Ϫ activity in oocytes required two cDNA transcripts, and the sequence analysis revealed that one is identical with the heavy chain of 4F2 cell surface antigen (4F2hc) and the other is a novel protein of 502 amino acids with 12 putative transmembrane domains. The latter protein, named xCT, showed a significant homology with those recently reported to mediate cationic or zwitterionic amino acid transport when co-expressed with 4F2hc. Thus xCT is a new member of a family of amino acid transporters that form heteromultimeric complex with 4F2hc, with a striking difference in substrate specificity. The expression of system x c Ϫ was highly regulated, and Northern blot analysis demonstrated that the expression of both 4F2hc and xCT was enhanced in macrophages stimulated by lipopolysaccharide or an electrophilic agent. However, the expression of xCT was more directly correlated with the system x c Ϫ activity.

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“…Then, the individual oocytes were washed five times with ice-cold Na ϩ -free uptake solution and transferred to Na ϩ -free uptake solution with or without nonradiolabeled L-leucine (18,33). The radioactivity in the medium and the remaining radioactivity in the oocytes were measured.…”

Section: Methodsmentioning

confidence: 99%

Identification and Functional Characterization of a Na+-independent Neutral Amino Acid Transporter with Broad Substrate Selectivity

Segawa¹,

Fukasawa²,

Miyamoto³

et al. 1999

Journal of Biological Chemistry

461

435

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We have isolated a cDNA from rat small intestine that encodes a novel Na ؉ -independent neutral amino acid transporter with distinctive characteristics in substrate selectivity and transport property. The encoded protein, designated L-type amino acid transporter-2 (LAT-2), shows amino acid sequence similarity to the system L Na ؉ -independent neutral amino acid transporter LAT-1 (Kanai, Y., Segawa, H., Miyamoto, K., Uchino, H., Takeda 273, 32437-32445). LAT-2 is a nonglycosylated membrane protein. It requires 4F2 heavy chain, a type II membrane glycoprotein, for its functional expression in Xenopus oocytes. LAT-2-mediated transport is not dependent on Na؉ or Cl ؊ and is inhibited by a system L-specific inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), indicating that LAT-2 is a second isoform of the system L transporter. Compared with LAT-1, which prefers large neutral amino acids with branched or aromatic side chains, LAT-2 exhibits remarkably broad substrate selectivity. It transports all of the L-isomers of neutral ␣-amino acids. LAT-2 exhibits higher affinity (K m ‫؍‬ 30 -50 M) to Tyr, Phe, Trp, Thr, Asn, Ile, Cys, Ser, Leu, Val, and Gln and relatively lower affinity (K m ‫؍‬ 180 -300 M) to His, Ala, Met, and Gly. In addition, LAT-2 mediates facilitated diffusion of substrate amino acids, as distinct from LAT-1, which mediates amino acid exchange. LAT-2-mediated transport is increased by lowering the pH level, with peak activity at pH 6.25, because of the decrease in the K m value without changing the V max value. Because of these functional properties and a high level of expression of LAT-2 in the small intestine, kidney, placenta, and brain, it is suggested that the heterodimeric complex of LAT-2 and 4F2 heavy chain is involved in the trans-cellular transport of neutral amino acids in epithelia and blood-tissue barriers.

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Obligatory Amino Acid Exchange via Systems bo,+-like and y+L-like

Cited by 162 publications

References 48 publications

Cloning and functional expression of a cDNA from rat jejunal epithelium encoding a protein (4F2hc) with system y+L amino acid transport activity

Cloning and functional expression of a cDNA from rat jejunal epithelium encoding a protein (4F2hc) with system y+L amino acid transport activity

Cloning and Expression of a Plasma Membrane Cystine/Glutamate Exchange Transporter Composed of Two Distinct Proteins

Identification and Functional Characterization of a Na+-independent Neutral Amino Acid Transporter with Broad Substrate Selectivity

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