Abstract
Mammalian cells possess a variety of amino acid-transport systems with overlapping substrate specificity. System L is one of the major amino acid-transport systems of non-epithelial cells. By expression cloning we have recently demonstrated that the surface antigen 4F2hc (CD98) is a necessary component for expression of system-L-like amino acid-transport activity in C6-BU-1 rat glioma cells [Bröer, Bröer and Hamprecht (1995) Biochem. J. 312, 863-870]. 4F2hc mRNA was detected in CHO cells, COS cells, activated lymphocytes isolated from mouse spleen and primary cultures of astrocytes. In all these cell types, Na+-independent isoleucine transport was mediated by system L. No contribution of system y+L to isoleucine or arginine transport was detected in C6-BU-1 cells. In lymphocytes, both system-L-like amino acid-transport activity and 4F2hc mRNA levels increased after treatment with phorbol ester plus ionomycin. Antisense oligonucleotides caused modest inhibition of Na+-independent isoleucine transport in C6-BU-1 cells and primary cultures of astroglial cells, whereas arginine transport was unaffected. Overexpression of 4F2hc cDNA in CHO cells resulted in an increase in Na+-independent isoleucine transport.
Full Text
The Full Text of this article is available as a PDF (316.6 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Arriza J. L., Kavanaugh M. P., Fairman W. A., Wu Y. N., Murdoch G. H., North R. A., Amara S. G. Cloning and expression of a human neutral amino acid transporter with structural similarity to the glutamate transporter gene family. J Biol Chem. 1993 Jul 25;268(21):15329–15332. [PubMed] [Google Scholar]
- Bertran J., Magagnin S., Werner A., Markovich D., Biber J., Testar X., Zorzano A., Kühn L. C., Palacin M., Murer H. Stimulation of system y(+)-like amino acid transport by the heavy chain of human 4F2 surface antigen in Xenopus laevis oocytes. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5606–5610. doi: 10.1073/pnas.89.12.5606. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bertran J., Werner A., Moore M. L., Stange G., Markovich D., Biber J., Testar X., Zorzano A., Palacin M., Murer H. Expression cloning of a cDNA from rabbit kidney cortex that induces a single transport system for cystine and dibasic and neutral amino acids. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5601–5605. doi: 10.1073/pnas.89.12.5601. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bröer S., Bröer A., Hamprecht B. Expression of Na+-independent isoleucine transport activity from rat brain in Xenopus laevis oocytes. Biochim Biophys Acta. 1994 Jun 1;1192(1):95–100. doi: 10.1016/0005-2736(94)90147-3. [DOI] [PubMed] [Google Scholar]
- Bröer S., Bröer A., Hamprecht B. The 4F2hc surface antigen is necessary for expression of system L-like neutral amino acid-transport activity in C6-BU-1 rat glioma cells: evidence from expression studies in Xenopus laevis oocytes. Biochem J. 1995 Dec 15;312(Pt 3):863–870. doi: 10.1042/bj3120863. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Calonge M. J., Gasparini P., Chillarón J., Chillón M., Gallucci M., Rousaud F., Zelante L., Testar X., Dallapiccola B., Di Silverio F. Cystinuria caused by mutations in rBAT, a gene involved in the transport of cystine. Nat Genet. 1994 Apr;6(4):420–425. doi: 10.1038/ng0494-420. [DOI] [PubMed] [Google Scholar]
- Chillarón J., Estévez R., Mora C., Wagner C. A., Suessbrich H., Lang F., Gelpí J. L., Testar X., Busch A. E., Zorzano A. Obligatory amino acid exchange via systems bo,+-like and y+L-like. A tertiary active transport mechanism for renal reabsorption of cystine and dibasic amino acids. J Biol Chem. 1996 Jul 26;271(30):17761–17770. doi: 10.1074/jbc.271.30.17761. [DOI] [PubMed] [Google Scholar]
- Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
- Christensen H. N. On the strategy of kinetic discrimination of amino acid transport systems. J Membr Biol. 1985;84(2):97–103. doi: 10.1007/BF01872207. [DOI] [PubMed] [Google Scholar]
- Christensen H. N. Role of amino acid transport and countertransport in nutrition and metabolism. Physiol Rev. 1990 Jan;70(1):43–77. doi: 10.1152/physrev.1990.70.1.43. [DOI] [PubMed] [Google Scholar]
- Closs E. I., Lyons C. R., Kelly C., Cunningham J. M. Characterization of the third member of the MCAT family of cationic amino acid transporters. Identification of a domain that determines the transport properties of the MCAT proteins. J Biol Chem. 1993 Oct 5;268(28):20796–20800. [PubMed] [Google Scholar]
- Devés R., Chavez P., Boyd C. A. Identification of a new transport system (y+L) in human erythrocytes that recognizes lysine and leucine with high affinity. J Physiol. 1992 Aug;454:491–501. doi: 10.1113/jphysiol.1992.sp019275. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Fei Y. J., Prasad P. D., Leibach F. H., Ganapathy V. The amino acid transport system y+L induced in Xenopus laevis oocytes by human choriocarcinoma cell (JAR) mRNA is functionally related to the heavy chain of the 4F2 cell surface antigen. Biochemistry. 1995 Jul 11;34(27):8744–8751. doi: 10.1021/bi00027a025. [DOI] [PubMed] [Google Scholar]
- Gottesdiener K. M., Karpinski B. A., Lindsten T., Strominger J. L., Jones N. H., Thompson C. B., Leiden J. M. Isolation and structural characterization of the human 4F2 heavy-chain gene, an inducible gene involved in T-lymphocyte activation. Mol Cell Biol. 1988 Sep;8(9):3809–3819. doi: 10.1128/mcb.8.9.3809. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hamprecht B., Löffler F. Primary glial cultures as a model for studying hormone action. Methods Enzymol. 1985;109:341–345. doi: 10.1016/0076-6879(85)09097-8. [DOI] [PubMed] [Google Scholar]
- Haynes B. F., Hemler M. E., Mann D. L., Eisenbarth G. S., Shelhamer J., Mostowski H. S., Thomas C. A., Strominger J. L., Fauci A. S. Characterization of a monoclonal antibody (4F2) that binds to human monocytes and to a subset of activated lymphocytes. J Immunol. 1981 Apr;126(4):1409–1414. [PubMed] [Google Scholar]
- Hemler M. E., Strominger J. L. Characterization of antigen recognized by the monoclonal antibody (4F2): different molecular forms on human T and B lymphoblastoid cell lines. J Immunol. 1982 Aug;129(2):623–628. [PubMed] [Google Scholar]
- Kanai Y., Smith C. P., Hediger M. A. The elusive transporters with a high affinity for glutamate. Trends Neurosci. 1993 Sep;16(9):365–370. doi: 10.1016/0166-2236(93)90094-3. [DOI] [PubMed] [Google Scholar]
- Kilberg M. S., Stevens B. R., Novak D. A. Recent advances in mammalian amino acid transport. Annu Rev Nutr. 1993;13:137–165. doi: 10.1146/annurev.nu.13.070193.001033. [DOI] [PubMed] [Google Scholar]
- Kim J. W., Closs E. I., Albritton L. M., Cunningham J. M. Transport of cationic amino acids by the mouse ecotropic retrovirus receptor. Nature. 1991 Aug 22;352(6337):725–728. doi: 10.1038/352725a0. [DOI] [PubMed] [Google Scholar]
- Lim K., Chae C. B. A simple assay for DNA transfection by incubation of the cells in culture dishes with substrates for beta-galactosidase. Biotechniques. 1989 Jun;7(6):576–579. [PubMed] [Google Scholar]
- Lindsten T., June C. H., Thompson C. B., Leiden J. M. Regulation of 4F2 heavy-chain gene expression during normal human T-cell activation can be mediated by multiple distinct molecular mechanisms. Mol Cell Biol. 1988 Sep;8(9):3820–3826. doi: 10.1128/mcb.8.9.3820. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Malandro M. S., Kilberg M. S. Molecular biology of mammalian amino acid transporters. Annu Rev Biochem. 1996;65:305–336. doi: 10.1146/annurev.bi.65.070196.001513. [DOI] [PubMed] [Google Scholar]
- Michalak M., Quackenbush E. J., Letarte M. Inhibition of Na+/Ca2+ exchanger activity in cardiac and skeletal muscle sarcolemmal vesicles by monoclonal antibody 44D7. J Biol Chem. 1986 Jan 5;261(1):92–95. [PubMed] [Google Scholar]
- Mora C., Chillarón J., Calonge M. J., Forgo J., Testar X., Nunes V., Murer H., Zorzano A., Palacín M. The rBAT gene is responsible for L-cystine uptake via the b0,(+)-like amino acid transport system in a "renal proximal tubular" cell line (OK cells). J Biol Chem. 1996 May 3;271(18):10569–10576. doi: 10.1074/jbc.271.18.10569. [DOI] [PubMed] [Google Scholar]
- Ohgimoto S., Tabata N., Suga S., Nishio M., Ohta H., Tsurudome M., Komada H., Kawano M., Watanabe N., Ito Y. Molecular characterization of fusion regulatory protein-1 (FRP-1) that induces multinucleated giant cell formation of monocytes and HIV gp160-mediated cell fusion. FRP-1 and 4F2/CD98 are identical molecules. J Immunol. 1995 Oct 1;155(7):3585–3592. [PubMed] [Google Scholar]
- Palacín M. A new family of proteins (rBAT and 4F2hc) involved in cationic and zwitterionic amino acid transport: a tale of two proteins in search of a transport function. J Exp Biol. 1994 Nov;196:123–137. doi: 10.1242/jeb.196.1.123. [DOI] [PubMed] [Google Scholar]
- Parmacek M. S., Karpinski B. A., Gottesdiener K. M., Thompson C. B., Leiden J. M. Structure, expression and regulation of the murine 4F2 heavy chain. Nucleic Acids Res. 1989 Mar 11;17(5):1915–1931. doi: 10.1093/nar/17.5.1915. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Quackenbush E. J., Gougos A., Baumal R., Letarte M. Differential localization within human kidney of five membrane proteins expressed on acute lymphoblastic leukemia cells. J Immunol. 1986 Jan;136(1):118–124. [PubMed] [Google Scholar]
- Quackenbush E., Clabby M., Gottesdiener K. M., Barbosa J., Jones N. H., Strominger J. L., Speck S., Leiden J. M. Molecular cloning of complementary DNAs encoding the heavy chain of the human 4F2 cell-surface antigen: a type II membrane glycoprotein involved in normal and neoplastic cell growth. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6526–6530. doi: 10.1073/pnas.84.18.6526. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rabito C. A., Karish M. V. Polarized amino acid transport by an epithelial cell line of renal origin (LLC-PK1). The basolateral systems. J Biol Chem. 1982 Jun 25;257(12):6802–6808. [PubMed] [Google Scholar]
- Rupp R. A., Snider L., Weintraub H. Xenopus embryos regulate the nuclear localization of XMyoD. Genes Dev. 1994 Jun 1;8(11):1311–1323. doi: 10.1101/gad.8.11.1311. [DOI] [PubMed] [Google Scholar]
- Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Segel G. B., Simon W., Lichtman M. A. Multicomponent analysis of amino acid transport in human lymphocytes. Diminished L-system transport in chronic leukemic B lymphocytes. J Clin Invest. 1984 Jul;74(1):17–24. doi: 10.1172/JCI111398. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shafqat S., Velaz-Faircloth M., Guadaño-Ferraz A., Fremeau R. T., Jr Molecular characterization of neurotransmitter transporters. Mol Endocrinol. 1993 Dec;7(12):1517–1529. doi: 10.1210/mend.7.12.7908408. [DOI] [PubMed] [Google Scholar]
- Shimbo K., Brassard D. L., Lamb R. A., Pinto L. H. Viral and cellular small integral membrane proteins can modify ion channels endogenous to Xenopus oocytes. Biophys J. 1995 Nov;69(5):1819–1829. doi: 10.1016/S0006-3495(95)80052-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shotwell M. A., Jayme D. W., Kilberg M. S., Oxender D. L. Neutral amino acid transport systems in Chinese hamster ovary cells. J Biol Chem. 1981 Jun 10;256(11):5422–5427. [PubMed] [Google Scholar]
- Shotwell M. A., Kilberg M. S., Oxender D. L. The regulation of neutral amino acid transport in mammalian cells. Biochim Biophys Acta. 1983 May 24;737(2):267–284. doi: 10.1016/0304-4157(83)90003-5. [DOI] [PubMed] [Google Scholar]
- Speciale C., Hares K., Schwarcz R., Brookes N. High-affinity uptake of L-kynurenine by a Na+-independent transporter of neutral amino acids in astrocytes. J Neurosci. 1989 Jun;9(6):2066–2072. doi: 10.1523/JNEUROSCI.09-06-02066.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Su T. Z., Logsdon C. D., Oxender D. L. Chinese hamster ovary mRNA-dependent, Na(+)-independent L-leucine transport in Xenopus laevis oocytes. Mol Cell Biol. 1992 Dec;12(12):5281–5287. doi: 10.1128/mcb.12.12.5281. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Su T. Z., Lunney E., Campbell G., Oxender D. L. Transport of gabapentin, a gamma-amino acid drug, by system l alpha-amino acid transporters: a comparative study in astrocytes, synaptosomes, and CHO cells. J Neurochem. 1995 May;64(5):2125–2131. doi: 10.1046/j.1471-4159.1995.64052125.x. [DOI] [PubMed] [Google Scholar]
- Tate S. S., Yan N., Udenfriend S. Expression cloning of a Na(+)-independent neutral amino acid transporter from rat kidney. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):1–5. doi: 10.1073/pnas.89.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thompson J. D., Higgins D. G., Gibson T. J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994 Nov 11;22(22):4673–4680. doi: 10.1093/nar/22.22.4673. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tzounopoulos T., Maylie J., Adelman J. P. Induction of endogenous channels by high levels of heterologous membrane proteins in Xenopus oocytes. Biophys J. 1995 Sep;69(3):904–908. doi: 10.1016/S0006-3495(95)79964-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Utsunomiya-Tate N., Endou H., Kanai Y. Cloning and functional characterization of a system ASC-like Na+-dependent neutral amino acid transporter. J Biol Chem. 1996 Jun 21;271(25):14883–14890. doi: 10.1074/jbc.271.25.14883. [DOI] [PubMed] [Google Scholar]
- Van Winkle L. J., Campione A. L., Gorman J. M. Na+-independent transport of basic and zwitterionic amino acids in mouse blastocysts by a shared system and by processes which distinguish between these substrates. J Biol Chem. 1988 Mar 5;263(7):3150–3163. [PubMed] [Google Scholar]
- Wang H., Kavanaugh M. P., North R. A., Kabat D. Cell-surface receptor for ecotropic murine retroviruses is a basic amino-acid transporter. Nature. 1991 Aug 22;352(6337):729–731. doi: 10.1038/352729a0. [DOI] [PubMed] [Google Scholar]
- Wang Y., Tate S. S. Oligomeric structure of a renal cystine transporter: implications in cystinuria. FEBS Lett. 1995 Jul 17;368(2):389–392. doi: 10.1016/0014-5793(95)00685-3. [DOI] [PubMed] [Google Scholar]
- Wells R. G., Hediger M. A. Cloning of a rat kidney cDNA that stimulates dibasic and neutral amino acid transport and has sequence similarity to glucosidases. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5596–5600. doi: 10.1073/pnas.89.12.5596. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wells R. G., Lee W. S., Kanai Y., Leiden J. M., Hediger M. A. The 4F2 antigen heavy chain induces uptake of neutral and dibasic amino acids in Xenopus oocytes. J Biol Chem. 1992 Aug 5;267(22):15285–15288. [PubMed] [Google Scholar]
- Woodlock T. J., Segel G. B., Lichtman M. A. Phorbol ester restores L-system amino acid transport of B lymphocytes in chronic lymphocytic leukemia. J Clin Invest. 1988 Jan;81(1):32–38. doi: 10.1172/JCI113306. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yao S. Y., Muzyka W. R., Elliott J. F., Cheeseman C. I., Young J. D. Poly(A)+ RNA from the mucosa of rat jejunum induces novel Na(+)-dependent and Na(+)-independent leucine transport activities in in oocytes of Xenopus laevis. Mol Membr Biol. 1994 Apr-Jun;11(2):109–118. doi: 10.3109/09687689409162228. [DOI] [PubMed] [Google Scholar]
- van den Hoff M. J., Moorman A. F., Lamers W. H. Electroporation in 'intracellular' buffer increases cell survival. Nucleic Acids Res. 1992 Jun 11;20(11):2902–2902. doi: 10.1093/nar/20.11.2902. [DOI] [PMC free article] [PubMed] [Google Scholar]