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01-01-2011 | Original Paper

Increased expression of l-amino acid transporters in balloon cells of tuberous sclerosis

Authors: Byung-Chan Lim, Kyu-Young Cho, Joon-Seop Lim, Rae-Seop Lee, Hyung-Seok Kim, Myeong-Kyu Kim, Jae-Hyoo Kim, Young-Jong Woo, Jong-Keun Kim, Do Kyung Kim, Hyung-Ihl Kim, Kyung-Wha Lee, Min-Cheol Lee

Published in: Child's Nervous System | Issue 1/2011

Abstract

Objects

Tuberous sclerosis complex (TSC) is a dysgenetic syndrome involved in multiple organs, and the pathognomonic cortical tuber act as an epileptic substrate. The amino acid transport system L (LAT) is a major nutrient transport system, and LAT1 is highly expressed in malignant tumors to support tumor cell growth. To study the life-long epilepsy from the cortical tuber, the expression of LAT1 in balloon cells and dysplastic neurons of the cortical tuber is investigated.

Materials and methods

LAT1 expression was investigated by LAT1 mRNA using reverse transcription-polymerase chain reaction and immunohistochemical staining with anti-human LAT1 antibody in nine patients with TSC and three control brains.

Conclusion

LAT1 mRNA was detectable only in fresh-frozen tissues of TSC, and it was upregulated in the cortical tuber lesion. While the LAT1 immunopositivity of control brains was limited in the capillary endothelial cells in the gray matter, increased LAT1 immunopositivity was noted in balloon cells of the cortical tubers in addition to the capillary endothelial cells as shown in control brains. Linear and strong immunopositivity along the cell membrane and cytoplasm of the balloon cells, and weakly granular immunopositivity in their cytoplasm were noted. Increased expression of LAT1 in the balloon cells is important for the active transport of large neutral amino acids into the balloon cells, and that the biologic process may play an important role in the active protein synthesis with metabolic maintenance of balloon cells in cortical tubers of patients with TSC.

Blondeau JP, Beslin A, Chantoux F, Francon J (1993) Triiodothyronine is a high-affinity inhibitor of amino acid transport system L1 in cultured astrocytes. J Neurochem 60:1407–1413CrossRefPubMed

Boado RJ, Li JY, Nagaya M, Zhang C, Pardridge WM (1999) Selective expression of the large neutral amino acid transporter at the blood-brain barrier. Proc Natl Acad Sci USA 96:12079–12084CrossRefPubMed

Campbell SL, Hablitz JJ (2008) Decreased glutamate transport enhances excitability in a rat model of cortical dysplasia. Neurobiol Dis 32:254–261CrossRefPubMed

Castagna M, Shayakul C, Trotti D, Sacchi VF, Harvey WR, Hediger MA (1997) Molecular characteristics of mammalian and insect amino acid transporters: implications for amino acid homeostasis. J Exp Biol 200:269–286PubMed

Christensen HN (1990) Role of amino acid transport and countertransport in nutrition and metabolism. Physiol Rev 70:43–77PubMed

Crino PB, Henske EP (1999) New developments in the neurobiology of the tuberous sclerosis complex. Neurology 53:1384–1390PubMed

del Amo EM, Urtti A, Yliperttula M (2008) Pharmacokinetic role of l-type amino acid transporters LAT1 and LAT2 european. J Pharm Sci 35:161–174

Gomes P, Soares-da-Silva P (1999) l-DOPA transport properties in an immortalized cell line of rat capillary cerebral endothelial cells, RBE 4. Brain Res 829:143–150CrossRefPubMed

Hiroshi N, Naoki O, Nariyoshi S, Shinji F, Hidetoshi O, Katsuji S, Hirotaka M, Yoshikatsu K, Endou H (2006) l-type amino acid transporter 1 as a potential molecular target in human astrocytic tumors. Int J Cancer 119:484–492CrossRef

10.

Hiroshi N, Naoki O, Nariyoshi S, Shinji F, Namiko N, Akiko Y, Katsuji S, Hirotaka M, Yoshikatsu K (2002) The role of CD98 in astrocytic neoplasms. Hum Cell 15:25–31CrossRef

11.

Hiroshi N, Naoki O, Youichi U, Hidetoshi O, Terushige T, Takamoto S, Hiroshi K, Nobusuke T, Akira O, Katsuji S, Nariyoshi S, Hirotaka M, Yoshikatsu K (2005) High expression of l-type amino acid transporter 1 in infiltrating glioma cells. Brain Tumor Pathol 22:89–91CrossRef

12.

Hirotaka M, Shingo T, Takahiro N, Arthit C, Kim DK, Cha SH, Jun I, Hiroshi Y, Jun F, Hitoshi E, Yoshikatsu K (2000) Expression of a system l neutral amino acid transporter at the blood-brain barrier. Neuropharm Neurotoxicol 169:3507–3511

13.

Kanai Y, Segawa H, Miyamoto K, Uchino H, Takeda E, Endou H (1998) Expression cloning and characterization of a transporter for large neutral amino acids activated by the heavy chain of 4F2 antigen (CD98). J Biol Chem 273:23629–23632CrossRefPubMed

14.

Kang NG, Chang HJ, Ok YC, Lee RS, Park SK, Lim JS, Cho KY, Kim HI, Kim JH, Oh HS, Lee MC (2007) Epileptogenic properties of balloon cells in cortical tubers of tuberous sclerosis: upregulation of drug resistance proteins. J Korean Neurosurg Soc 41:397–402

15.

Kim DK, Kim IJ, Hwang S, Kook JH, Lee MC, Shin BA, Bae CS, Yoon JH, Ahn SG, Kim SA, Yoshikatsu K, Hitoshi E, Kim JK (2004) System l-amino acid transporters are differently expressed in rat astrocyte and C6 glioma cells. Neurosci Res 50:437–446CrossRefPubMed

16.

Kim SG, Kim HH, Kim HK, Kim CH, Chun HS, Kanai Y, Endou H, Kim DK (2006) Differential expression and functional characterization of system l amino acid transporters in human normal osteoblast cells and osteogenic sarcoma cells. Anticancer Res 26:1989–1996PubMed

17.

Kobayashi K, Ohnishi A, Promsuk J, Shimizu S, Kanai Y, Shiokawa Y, Nagane M (2008) Enhanced tumor growth elicited by l-type amino acid transporter 1 in human malignant glioma cells. Neurosurgery 62:493–504CrossRefPubMed

18.

Kuniaki N, Hirotaka M, Yoshikatsu K, Hitoshi E, Hi S, Susumu T, Makio M, Eiji I, Yuichi O, Shinsuke A, Toshiaki K (2006) LAT1 expression in normal lung and in atypical adenomatous hyperplasia and adenocarcinoma of the lung. Virchows Arch 448:142–150CrossRef

19.

Kuzniecky RI, Barkovich AJ (1996) Pathogenesis and pathology of focal malformations of cortical development and epilepsy. J Clin Neurophysiol 13:468–480CrossRefPubMed

20.

Kyoichi K, Noboru O, Hisao I, Kimihiro S, Noriko Y, Noriaki S, Takeshi H, Osamu K, Hironobu I, Tamotsu I, Yoshikatsu K, Hitoshi E, Takashi N, Masatomo M (2008) Expression of l-type amino acid transporter 1 (LAT1) in neuroendocrine tumors of the lung. Pathol Res Pract 204:553–561CrossRef

21.

Lee MC, Kim KM, Woo YJ, Kim MK, Kim JH, Nam SC, Suh JJ, Chung WK, Lee JS, Kim HI, Choi HY, Kim SU (2001) Pathogenic significance of neuronal migration disorders in temporal lobe epilepsy. Human Pathol 32:643–648CrossRef

22.

Mastroberardino L, Spindler B, Pfeiffer R, Skelly PJ, Loffing J, Shoemaker CB, Verrey F (1998) Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family. Nature 395:288–291CrossRefPubMed

23.

Nakamura E, Sato M, Yang H, Miyagawa F, Harasaki M, Tomita K, Matsuoka S, Noma A, Iwai K, Minato N (1999) 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 274:3009–3016CrossRefPubMed

24.

Oh HS, Lee MC, Kim HS, Lee JS, Lee JH, Kim MK, Woo YJ, Kim JH, Kim HI, Kim SU (2008) Pathophysiologic characteristics of balloon cells in cortical dysplasia. Childs Nerv Syst 24:175–183CrossRefPubMed

25.

Park NS, Kim SG, Kim HK, Moon SY, Kim CS, Cho SH, Kanai Y, Endou H, Kim DK (2008) Characterization of amino acid transport system L in HTB-41 human salivary gland epidermoid carcinoma cells. Anticancer Res 28:2649–2655PubMed

26.

Pfeiffer R, Spindler B, Loffing J, Skelly PJ, Shoemaker CB, Verrey F (1998) Functional heterodimeric amino acid transporters lacking cysteine residues involved in disulfide bond. FEBS Lett 439:157–162CrossRefPubMed

27.

Piedimonte LR, Wailes IK, Weiner HL (2006) Tuberous sclerosis complex: molecular pathogenesis and animal models. Neurosurg Focus 20:E4CrossRefPubMed

28.

Pineda M, Fernandez E, Torrents D, Estevez R, Lopez C, Camps M, Lloberas J, Zorzano A, Palacin M (1999) 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 274:19738–19744CrossRefPubMed

29.

Raymond AA, Fish DR, Sisodiya SM, Alsanjari N, Stevens JM, Shorvon SD (1995) Abnormalities of gyration, heterotopias, tuberous sclerosis, focal cortical dysplasia, microdysgenesis, dysembryoplastic neuroepithelial tumour and dysgenesis of the archicortex in epilepsy. Clinical, EEG, and neuroimaging features in 100 adult patients. Brain 118:629–660CrossRefPubMed

30.

Rossier G, Meier C, Bauch C, Summa V, Sordat B, Verrey F, Kuhn LC (1999) LAT2, a new basolateral 4F2hc/CD98-associated amino acid transporter of kidney and intestine. J Biol Chem 274:34948–34954CrossRefPubMed

31.

Sancak O, Nellist M, Goedbloed M, Elfferich P, Wouters C, Maat-Kievit A, Zonnenberg B, Verhoef S, Halley D, van den Ouweland A (2001) Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 68:64–80CrossRef

32.

Sancak O, Nellist M, Goedbloed M, Elfferich P, Wouters C, Maat-Kievit A, Zonnenberg B, Verhoef S, Halley D, van den Ouweland A (2005) Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype-phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex. Eur J Hum Genet 13:731–741CrossRefPubMed

33.

Segawa H, Fukasawa Y, Miyamoto K, Takeda E, Endou H, Kanai Y (1999) Identification and functional characterization of a Na + -independent neutral amino acid transporter with broad substrate selectivity. J Biol Chem 274:19745–19751CrossRefPubMed

34.

Su TZ, Lunney E, Campbell G, Oxender DL (1995) 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 64:2125–2131CrossRefPubMed

35.

Thom M, Martinian L, Sisodiya SM, Cross JH, Williams G, Stoeber K, Harkness W, Harding BN (2005) Mcm2 labelling of balloon cells in focal cortical dysplasia. Neuropathol Appl Neurobiol 31:580–588CrossRefPubMed

36.

Yanagida O, Kanai Y, Chairoungdua A, Kim DK, Segawa H, Nii T, Cha SH, Matsuo H, Fukushima J, Fukasawa Y, Tani Y, Taketani Y, Uchino H, Kim JY, Inatomi J, Okayasu I, Miyamoto K, Takeda E, Goya T, Endou H (2001) Human l-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. Biochim Biophys Acta 1514:291–302CrossRefPubMed

Title: Increased expression of l-amino acid transporters in balloon cells of tuberous sclerosis
Authors: Byung-Chan Lim
Kyu-Young Cho
Joon-Seop Lim
Rae-Seop Lee
Hyung-Seok Kim
Myeong-Kyu Kim
Jae-Hyoo Kim
Young-Jong Woo
Jong-Keun Kim
Do Kyung Kim
Hyung-Ihl Kim
Kyung-Wha Lee
Min-Cheol Lee
Publication date: 01-01-2011
Publisher: Springer-Verlag
Published in: Child's Nervous System / Issue 1/2011
Print ISSN: 0256-7040
Electronic ISSN: 1433-0350
DOI: https://doi.org/10.1007/s00381-010-1239-2

At a glance: The STEP trials

Springer Medicine

Increased expression of l-amino acid transporters in balloon cells of tuberous sclerosis

Abstract

Objects

Materials and methods

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Objects

Materials and methods

Conclusion

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