Abstract

In order to understand the renal reabsorption mechanism of neutral amino acids via amino acid transporters, we have isolated human L-type amino acid transporter 2 (hLAT2) and human T-type amino acid transporter 1 (hTAT1) in human, then, we have examined and compared the gene structures, the functional characterizations and the localization in human kidney. Northern blot analysis showed that hLAT2 mRNA was expressed at high levels in the heart, brain, placenta, kidney, spleen, prostate, testis, ovary, lymph node and the fetal liver. The hTAT1 mRNA was detected at high levels in the heart, placenta, liver, skeletal muscle, kidney, pancreas, spleen, thymus and prostate. Immunohistochemical analysis on the human kidney revealed that the hLAT2 and hTAT1 proteins coexist in the basolateral membrane of the renal proximal tubules. The hLAT2 transports all neutral amino acids and hTAT1 transports aromatic amino acids. The basolateral location of the hLAT2 and hTAT1 proteins in the renal proximal tubule as well as the amino acid transport activity of hLAT2 and hTAT1 suggests that these transporters contribute to the renal reabsorption of neutral and aromatic amino acids in the basolateral domain of epithelial proximal tubule cells, respectively. Therefore, LAT2 and TAT1 play essential roles in the reabsorption of neutral amino acids from the epithelial cells to the blood stream in the kidney. Because LAT2 and TAT1 are essential to the efficient absorption of neutral amino acids from the kidney, their defects might be involved in the pathogenesis of disorders caused by a disruption in amino acid absorption such as blue diaper syndrome.

주제어

#L-Type amino acid transporter 2 (LAT2)   #T-Type amino acid transporter 1(TAT1)   #Amino acids   #Reabsorption mechanism   #Kidney  

저자의 다른 논문

참고문헌 (44)

1. Lakshmanan, M., Goncalves, E., Lessly, G., Foti, D., and Robbins, J., The transport of thyroxine into mouse neuroblastoma cells, NB41A3: the effect of L-system amino acids. Endocrinology, 126, 3245-3250 (1990) 
2. Mizoguchi, K., Cha, S. H., Chairoungdua, A., Kim, D. K., Shigeta, Y., Matsuo, H., Fukushima, J., Awa, Y., Akakura, K., Goya, T., Ito, H., Endou, H., and Kanai, Y., Human cystinuriarelated transporter: localization and functional characterization. Kidney Int., 59, 1821-1833 (2001) 
3. Nii, T., Segawa, H., Taketani, Y., Tani, Y., Ohkido, M., Kishida, S., Ito, M., Endou, H., Kanai, Y., Takeda, E., and Miyamoto, K., Molecular events involved in up-regulating human $Na^+$- independent neutral amino acid transporter LAT1 during Tcell activation. Biochem. J., 358, 693-704 (2001) 
4. Oxender, D. L. and Christensen, H. N., Evidence for two types of mediation of neutral amino acid transport in Ehrlich cells. Nature, 197, 765-767 (1963) 
5. Peghini, P., Janzen, J., and Stoffel, W., Glutamate transporter EAAC-1-deficient mice develop dicarboxylic aminoaciduria and behavioral abnormalities but no neurodegeneration. EMBO J., 16, 3822-3832 (1997) 
6. Pfeiffer, R., Spindler, B., Loffing, J., Skelly, P. J., Shoemaker, C. B., and Verrey, F., Functional heterodimeric amino acid transporters lacking cysteine residues involved in disulfide bond. FEBS Lett., 439, 157-162 (1998) 
7. Prasad, P. D., Wang, H., Huang, H., Kekuda, R., Rajan, D. P., Leibach, F. H., and Ganapathy, V., Human LAT1, a subunit of system L amino acid transporter: molecular cloning and transport function. Biochem. Biophys. Res. Commun., 255, 283-288 (1999) 
8. Rosenberg, R., Young, J. D., and Ellory, J. C., L-tryptophan transport in humanred blood cells. Biochim. Biophys. Acta, 598, 375-384 (1980) 
9. Su, T. Z., Lunney, E., Campbell, G., and 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., 64, 2125-2131 (1995) 
10. Utsunomiya-Tate, N., Endou, H., and Kanai, Y., Cloning and functional characterization of a system ASC-like $Na^+$- dependent neutral amino acid transporter. J. Biol. Chem., 271, 14883-14890 (1996) 
11. Yanagida, O., Kanai, Y., Chairoungdua, A., Kim, D. K., Segawa, H., Nii, T., Cha, S. H., Matsuo, H., Fukushima, J., Fukasawa, Y., Tani, Y., Taketani, Y., Uchino, H., Kim, J. Y., Inatomi, J., Okayasu, I., Miyamoto, K., Takeda, E., Goya, T., and Endou, H., Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. Biochim. Biophys. Acta, 1514, 291-302 (2001) 
12. Christensen, H. N., Role of amino acid transport and countertransport in nutrition and metabolism. Physiol. Rev., 70, 43-77 (1990) 
13. Chillaron, J., Estevez, R., Mora, C., Wagner, C. A., Suessbrich, H., Lang, F., Gelpi, J. L., Testar, X., Busch, A. E., Zorzano, A., and Palacin, M., Obligatory amino acid exchange via systems $b^{o,+}$-like and $y^+L-like$. A tertiary active transport mechanism for renal reabsorption of cystine and dibasic amino acids. J. Biol. Chem., 271, 17761-17770 (1996) 
14. Hirokawa, T., Boon-Chieng, S., and Mitaku, S., SOSUI: classification and secondary structure prediction system for membrane proteins. Bioinformatics, 14, 378-379 (1998) 
15. Palacin, M., Estevez, R., Bertran, J., and Zorzano, A., Molecular biology of mammalian plasma membrane amino acid transporters. Physiol. Rev., 78, 969-1054 (1998) 
16. Altman, A., Cardenas, J. M., Houghten, R. A., Dixon, F. J., and Theofilopoulos, A. N., Antibodies of predetermined specificity against chemically synthesized peptides of human interleukin 2. Proc. Natl. Acad. Sci. U.S.A., 81, 2176-2180 (1984) 
17. Goldenberg, G. J., Lam, H. Y., Begleiter, A., Active carriermediated transport of melphalan by two separate amino acid transport systems in LPC-1 plasmacytoma cells in vitro. J. Biol. Chem., 254, 1057-1064 (1979) 
18. Heng, H. H. Q. and Tsui, L. -C., Modes of DAPI banding and simultaneously in situ hybridization. Chromosoma, 102, 325– 332 (1993) 
19. Kim, D. K., Kanai, Y., Chairoungdua, A., Matsuo, H., Cha, S. H., and Endou, H., Expression cloning of a $Na^+-independent$ aromatic amino acid transporter with structural similarity to $H^+$/monocarboxylate transporters. J. Biol. Chem., 276, 17221-17228 (2001) 
20. Lee, S. H., Chae, K. S., and Sohn, D. H., Identification of expressed sequence tags of genes expressed highly in the activated hepatic stellate cell. Arch. Pharm. Res., 27, 422- 428 (2004)  원문보기 상세보기
21. Segawa, H., Fukasawa, Y., Miyamoto, K., Takeda, E., Endou, H., and Kanai, Y., Identification and functional characterization of a $Na^+$-independent neutral amino acid transporter with broad substrate selectivity. J. Biol. Chem., 274, 19745- 19751 (1999) 
22. Wolf, D. A., Wang, S., Panzia, M. A., Bassily, N. H., and Thompson, N. L., Expression of a highly conserved oncofetal gene, TA1/E16, in human colon carcinoma and other primary cancers: homology to Schistosoma mansoni amino acid permease and Caenorhabditis elegans gene products. Cancer Res., 56, 5012-5022 (1996) 
23. Hisano, S., Haga, H., Miyamoto, K., Takeda, E., and Fukui, Y., The basic amino acid transporter (rBAT)-like immunoreactivity in paraventricular and supraoptic magnocellular neurons of the rat hypothalamus. Brain Res., 710, 299-302 (1996) 
24. Kanai, Y., Segawa, H., Miyamoto, K., Uchino, H., Takeda, E., and Endou, H., Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J. Biol. Chem., 273, 23629-23632 (1998) 
25. Gomes, P. and Soares-da-Silva, P., L-DOPA transport properties in an immortalized cell line of rat capillary cerebral endothelial cells, RBE 4. Brain Res., 829, 143-150 (1999) 
26. Heng, H. H. Q., Squire, J., and Tsui, L. -C., High resolution mapping of mammalian genes by in situ hybridization to free chromosome. Proc. Natl. Acad. Sci. U.S.A., 89, 9509–9513 (1992) 
27. Rossier, G., Meier, C., Bauch, C., Summa, V., Sordat, B., Verrey, F., and Kuhn, L. C., LAT2, a new basolateral 4F2hc/ CD98-associated amino acid transporter of kidney and intestine. J. Biol. Chem., 274, 34948-34954 (1999) 
28. Yoon, J. H., Kim, Y. B., Kim, M. S., Park, J. C., Kook, J. K., Jung, H. M., Kim, S. G., Yoo, H., Ko, Y. M., Lee, S. H., Kim, B. Y., Chun, H. S., Kanai, Y., Endou, H., and Kim, D. K., Expression and functional characterization of the system L amino acid transporter in KB human oral epidermoid carcinoma cells. Cancer Lett., 205, 215-226 (2004) 
29. Kim, D. K., Kanai, Y., Matsuo, H., Kim, J. Y., Chairoungdua, A., Kobayashi, Y., Enomoto, A., Cha, S. H., Goya, T., and Endou, H., The human T-type amino acid transporter-1: characterization, gene organization, and chromosomal location. Genomics, 79, 95-103 (2002b) 
30. Utsunomiya-Tate, N., Endou, H., and Kanai, Y., Tissue specific variants of glutamate transporter GLT-1. FEBS Lett., 416, 312-316 (1997) 
31. Stevens, B. R., Kaunitz, J. D., and Wright, E. M., Intestinal transport of amino acids and sugars: advances using membrane vesicles. Annu. Rev. Physiol., 46, 417-433 (1984) 
32. Kim, D. K., Kanai, Y., Choi, H. W., Tangtrongsup, S., Chairoungdua, A., Babu, E., Tachampa, K., Anzai, N., Iribe, Y., and Endou, H., Characterization of the system L amino acid transporter in T24 human bladder carcinoma cells. Biochim. Biophys. Acta, 1565, 112-121 (2002a) 
33. Sang, J., Lim, Y. -P., Panzia, M., Finch, P., and Thompson, N. L., TA1, a highly conserved oncofetal complementary DNA from rat hepatoma, encodes an integral membrane protein associated with liver development, carcinogenesis, and cell activation. Cancer Res., 55, 1152-1159 (1995) 
34. Broer, A., Klingel, K., Kowalczuk, S., Rasko, J. E., Cavanaugh, J., and Broer, S., Molecular cloning of mouse amino acid transport system $B^0$, a neutral amino acid transporter related to Hartnup disorder. J. Biol. Chem., 279, 24467-24476 (2004) 
35. Mannion, B. A., Kolesnikova, T. V., Lin, S. -H., Thompson, N. L., and Hemler, M. E., The light chain of CD98 is identified as E16/TA1 protein. J. Biol. Chem., 273, 33127-33129 (1998) 
36. Silbernagl, S., Renal transport of amino acids. Klin. Wochenschr., 57, 1009-1019, (1979) 
37. Lee, S. H., Chae, K. S., Nan, J. X., and Sohn, D. H., The increment of purine specific sodium nucleoside cotransporter mRNA in experimental fibrotic liver induced by bile duct ligation and scission. Arch. Pharm. Res., 23, 613-619 (2000) 
38. Shayakul, C., Kanai, Y., Lee, W. S., Brown, D., Rothstein, J. D., and Hediger, M. A., Localization of the high-affinity glutamate transporter EAAC1 in rat kidney. Am. J. Physiol., 273, F1023- F1029 (1997) 
39. Nakamura, E., Sato, M., Yang, H., Miyagawa, F., Harasaki, M., Tomita, K., Matsuoka, S., Noma, A., Iwai, K., and Minato, N., 4F2 (CD98) heavy chain is associated covalently with an amino acid transporter and controls intracellular trafficking and membrane topology of 4F2 heterodimer. J. Biol. Chem., 274, 3009-3016 (1999) 
40. Kanai, Y. and Hediger, M. A., Primary structure and functional characterization of a high-affinity glutamate transporter. Nature, 360, 467-471 (1992) 
41. Pineda, M., Fernandez, E., Torrents, D., Estevez, R., Lopez, C., Camps, M., Lloberas, J., Zorzano, A., and Palacin, M., Identification of a membrane protein, LAT-2, that Co-expresses with 4F2 heavy chain, an L-type amino acid transport activity with broad specificity for small and large zwitterionic amino acids. J. Biol. Chem., 274, 19738-19744 (1999) 
42. Blondeau, J. P., Beslin, A., Chantoux, F., and Francon, J., Triiodothyronine is a high-affinity inhibitor of amino acid transport system L1 in cultured astrocytes. J. Neurochem., 60, 1407-1413 (1993) 
43. van Winkle, L. J., Mann, D. F., Campione, A. L., and Farrington, B. H., Transport of benzenoid amino acids by system T and four broad scope systems in preimplantation mouse conceptuses. Biochim. Biophys. Acta, 1027, 268–277 (1990) 
44. Kanai, Y. and Endou, H., Heterodimeric amino acid transporters: molecular biology and pathological and pharmacological relevance. Curr. Drug Metab., 2, 339-354 (2001) 

이 논문을 인용한 문헌 (0)

1. 이 논문을 인용한 문헌 없음