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1999 Fiscal Year Final Research Report Summary

Molecular mechanisms of the organic anion permeation through blood-brain barrier

Research Project

Project/Area Number 10670096
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field General pharmacology
Research InstitutionKyorin University

Principal Investigator

KANAI Yoshikatsu  Kyorin University, School of Medicine, Associate Professor, 医学部, 助教授 (60204533)

Co-Investigator(Kenkyū-buntansha) SEKINE Takashi  Kyorin University, School of Medicine, Assistant, 医学部, 助手 (50255402)
Project Period (FY) 1998 – 1999
KeywordsTransporter / Organic anion / Blood-brain barrier / Amino acid / Sulfate conjugate / Endothelial cell / Trans-cellular Transport / Pharmacodynamics
Research Abstract

The major component of the blood-brain barrier is the tightly sealed brain capillary endothelial cells which form a permeation barrier for hydrophilic compounds. To provide brain tissues with essential nutrients such as sugars and amino acids, the blood-brain barrier is, thus, equipped with specialized transport systems. The amino acid transport systems are also important as a permeation path for amino acid-related drugs. Blood-brain barrier possesses transport systems for organic anions. This system is proposed to be essential to extrude monoamine metabolites and conjugated compounds formed in the brain tissues. The purpose of this study is to identify molecular nature of the transport systems for organic anions and amino acids.
Based on the sequence homology to the organic anion transporter OAT1, we identified novel organic anion transporters OAT2, OAT3 and OAT4 and established an organic anion transporter family. OAT1 was present in astrocyte processes surrounding capillaries. OAT1 is, thus, proposed to mediate the transfer of organic anions from astrocytes to capillary endothelial cells, which is critical for the excretion of anionic metabolites produced in neurones. OAT3 accepts conjugated compounds as its substrates. It would, therefore, be suitable as an organic anion transporting system in the blood-brain barrier.
We identified system L transporters, LAT1 and LAT2, which associate with single membrane spanning protein, 4F2hc. We further found transporters related LAT1 and established the heterodimeric amino acid transporter family. By gencrating specific antibodies against LAT1, LAT2 and 4F2hc, we showed that these proteins exist on the brain capillary endothelial cells. These proteins were found to be present in the luminal and abluminal membranes. Thus, both LAT1 and LAT2 are proposed to play critical roles in the permeation of amino acids and amino acid related drugs through the blood-brain barrier.

  • Research Products

    (60 results)

All Other

All Publications (60 results)

  • [Publications] Chairoungdua A.: "Identification of an amino acid transporter associated with the cystimuria-related type II membrane glycoprotein"J. Biol. Chem.. 274. 28845-28848 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Jariyawat S.: "The interaction and transporter of b-lactam antibiotics with the cloned rat renal organic anion transporter 1"J.Pharmacol. Exp. Ther. 290. 672-677 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Oku A.: "T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes"Diabetes. 48. 1794-1800 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Igarashi T.: "Mutations in SLC4A4 cause permanentisolated proximal renal tubular acidosis with ocularabnormalities"Nature Genet.. 23. 264-266 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Takeda M.: "Role of organic anion transporter 1 (OAT1) in cephaloridine (CER)-induced nephrotoxicity"Kidney Int.. 56. 2128-2136 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Okuda T.: "Identification and characterization of the high-affinity choline transporter"Nature Neurosci.. 3. 120-125 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hosoyamada M.: "Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney"Am. J. Physiol.. 276. F122-F128 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tojo A.: "Immunohistochemical localization of multispecific renal organic anion transporter 1 in rat kidney"J. Am. Soc. Nephrol.. 10. 464-471 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kusuhara H.: "Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain"J. Boil. Chem.. 274. 13675-13680 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Apiwattnakul N.: "Transport properties of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes"Mol. Pharmacol.. 55. 847-854 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tsuda M.: "Transport of ochratoxin A by renal multispecific organic anion transporter 1"J. Pharmacol. Exp. Ther.. 289. 1301-1305 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Segawa H.: "Identification and functional characterization of a Na+-independent neutral amino acid transporter with broad substrate selectivity"J. Boil. Chem.. 274. 19745-19751 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 金井好克: "グルタミン酸トランスポーター"Clinical Neuroscience. 18. 124-125 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 金井好克: "モノアミントランスポーター"Clinical Neuroscience. 18. 246-247 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 金井好克: "血液・脳関門トランスポーター"Clinical Neuroscience. 18. 368-369 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 金井好克: "グルタミン酸トランスポーターの機能特性"Brain Medical. 12. 161-168 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 金井好克: "アミノ酸トランスポーターの構造・機能とその病態"Mebio. 15. 105-112 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Romero M: "Expression cloning using Xenopus laevis oocytes"Methods Enzymol.. 296. 17-52 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Cha S.H: "Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta"J. Biol. Chem. 275. 4507-4512 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Fukasawa Y.: "Identification and characterization of a Na^+-independent neutral amino acid transporter that associates with the 4F2 heavy chain and exhibits substrate selectivity for small neutral D- and L-amino acids"J. Biol. Chem. 275. 9690-9698 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakajima N.: "Developmental changes in multispecific organic anion transporter 1 expression in the rat kidney"Kidney Int.. 57. 1608-1616 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 金井好克: "アミノ酸輸送体:アミノ酸尿症"BIO Clinica. 14. 879-883 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 金井好克: "Na^+依存性アミノ酸トランスポーター"生体の科学. 50. 291-297 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sekine T.: "Molecular biology of multispecific organic anion transporter family (OAT family)"Clin. Exp. Nephrol.. 3. 237-243 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 金井好克: "トランスポーターの薬理"神経研究の進歩. 296. 17-52 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 金井好克: "機能を手ががりにしたクローニング"腎と透析、1998臨時増刊号『分子腎臓病学』. 66-70 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 金井好克: "Na^+/グルコース共輸送体"腎と透析 1998臨時増刊号『分子腎臓病学』. 232-237 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sekine T.: "Identification of multispecific organic anion transporter 2 expressed predominantly in the liver"FEBS Lett.. 429. 179-182 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sekine T.: "Cloning, functional characterization and localization of a rat renal NA^+-dicarboxylate transporter"Am. J. Physiol. 275. F298-F305 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kanai Y.: "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)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sekine T.: "Molecular cloning and characterization of high-affinity carnitine transporter from rat intestine"Biochem. Biophys. Res. Commun.. 251. 586-591 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kanai Y.: "Transport properties of a system y^+L neutral and basic amino acid transporter : Insights into the mechanisms of substrate recognition"J. Biol. Chem.. 275. 20787-20793 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakauchi J.: "Cloning and characterization of a human brain Na^+-independent transporter for small neutral amino acids that transports D-serine with high affinity"Neurosci. Lett.. 287. 231-238 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Ishii H.: "Involvement of rBAT in Na^+-dependent and -independent transport of the neurotransmitter candidate L-DOPA in Xenopus laevis oocytes injected with rabbit small intestinal epithelium poly A^+RNA"Biochem. Biophys. Acta. 1466. 61-70 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsuo H.: "Mouse Asc-1 (asc-type amino acid transporter 1) maps to chromosome 7, region B1-B5"Chromosome Res.. 8. 456 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Wada S.: "Rat multispeciffic organic anion transporter 1 (OAT1) transports zidovudine, acyclovir and antiviral nucleoside analogs"J. Pharmacol. Exp. Ther.. 294. 844-849 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Matsuo H.: "Expression of a system L neutral amino acid transporter at the blood-brain barrier"Neuro report. 11. 3507-3511 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tsuganezawa H: "A new member of the HCO_3-transporter superfamily is an apical anion exchanger of β-Intercalated Cells in the kidney"J. Biol. Chem.. (in press).

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 金井好克: "アミノ酸トランスポーター:基質認識の多様性を生みだす分子基盤シリーズ・ニューバイオフィジックスII:第3巻「ポンプとトランスポーター」"共立出版. 19 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 金井好克: "神経伝達物質トランスポーター/Annual Review神経2000"中央医学社. 7(21-27) (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 金井好克: "グルタミン酸トランスポーター分子の機能と病態/グルタミン酸最新の話題"Excerpta Medica. 29 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Sekine, T, Cha, S- H, Tsuda, M, Aptiwattanakul, N, Nakajima, N, Kanai, Y, and Endou, H: "Identification of multispecific organic anion transporter 2 expressed predominantly in the liver"FEBS Lett.. 429. 179-182 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sekine, T, Cha, S- H, Hosoyamada, M, Kanai, Y, Watanabe, N, Furuta, Y, Fukuda, K, Igarashi, T, and Endou, H: "Cloning functional characterization and localization of a rat renal NaィイD1+ィエD1-dicarboxylate transporter"Am. J. Physiol.. 275. F298-F305 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] 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)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Sekine, T, Kusuhara, H, Utsunomiya-Tate, N, Tsuda, M, Sugiyama, Y, Kanai, Y, and Endou H: "Molecular cloning and characterization of high-affinity carnitine transporter from rat intestine"Biochem. Biophys. Res. Commun.. 251. 586-591 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hosoyamada, H, Sekine, T, Kanai, Y, and Endou H: "Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney"Am. J. Physiol., (Renal Physiol.). 276, (45). F122-F128 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tojo, A, Sekine, T, Nakajima, N, Hosoyamada, M, Kanai, Y, Kimura, K, and Endou, H: "Immunohistochemical localization of multispecific renal organic anion transporter 1 in rat kidney"J. Am. Soc Nephrol.. 10. 464-471 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kusuhara, H, Sekine, T, Utsunomiya-Tate, N, Tsuda, M, Kojima, R, Cha, S-H, Sugiyama, Y, Kanai, Y, and Endou H: "Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain"J. Biol. Chem.. 274. 13675-13680 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Apiwattnakul, N, Sekine, T, Chairoungdua, A, Kanai, Y, Nakajima, N, Sophasan, S, and Endou H: "Transport properties of nonsteroidal anti-inflammatory drugs by organic anion transporter 1 expressed in Xenopus laevis oocytes"Mol. Pharmacol.. 55. 847-845 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsuda, M, Sekine, T, Takeda, M, Cha, SH, Kanai, Y, Kimura, M and Endou, H: "Transport of ochratoxin A by renal multispecific organic anion transporter 1"J. Pharmacol. Exp. Ther.. 289. 1301-1305 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Segawa, H, Fukusawa, Y, Miyamoto, K, Takeda, E, Endou, H, and Kanai, Y: "Identification and functional characterization of a NaィイD1+ィエD1-independent neutral amino acid transporter with broad substrate selectivity"J. Biol. Chem.. 274. 19745-19751 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Chairoungdua, A, Segawa, H, Kim, JY, Miyamoto, K, Haga, H, Fukui, Y, Mizoguchi, K, Ito, H, Takeda, E, Endou, H, and Kanai, Y: "Identification of an amino acid transporter associated with the cystinuria-related type II membrane glycoprotein"J. Biol. Chem.. 274. 28845-28848 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Jariyawat, S, Sekine, T, Takeda, M, Apiwattnakul, N, Kanai, Y, Sophasan, S, and Endou, H: "The interaction and transporter of b-lactam antibiotics with the cloned rat renal organic anion transporter"J. Pharmacol. Exp. Ther.. 290. 672-677 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Oku, A, Ueda, K, Arakawa, K, Ishihara, T, Nawano, M, Matsumoto, M, Saito, A, Tsujihara, K, Anai, M, Asano, T, Kanai, Y and Endou, H: "T-1095, an inhibitor of renal NaィイD1+ィエD1-glucose cotransporters, may provide a novel approach to treating diabetes"Diabetes. 48. 1794-1800 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Igarashi, T, Inatomi, J, Sekine, T, Cha, SH, Kanai, Y, Kunimi, M, Tsukamoto, K, Satoh, H, Shimadzu, M, Tozawa, F, Mori, T, Shiobara, M, Seki, G, Endou, H: "Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities"Nature Genet. 23. 264-266 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Takeda, M, Tojo, A, Sekine, T, Hosoyamada, M, Kanai, Y, and Endou, H: "Role of organic anion transporter 1 (OAT1) in cephaloridine (CER)-induced nephrotoxicity"Kidney Int.. 56. 2128-2136 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Okuda, T, Haga, T, Kanai, Y, Endou, H, Ishihara, T, and Katsura, I: "Identification and characterization of the high-affinity choline transporter"Nature Neurosci.. 3. 120-125 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Cha, SH, Sekine, T, Kusuhara, H, Yu, E, Kim, JY, Kim, DK, Sugiyama, Y, Kanai, Y, and Endou, H: "Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta"J. Biol. Chem.. 275. 4507-4512 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Fukasawa, Y, Segawa, H, Kim, JY, Chairoungdua, A, Kim, DK, Matsuo, H, Cha, SH, Endou, H, and Kanai, Y: "Identification and characterization of a NaィイD1+ィエD1-independent neutral amino acid transporter that associates with the 4F2 heavy chain and exhibits substrate selectivity for small neutral D- and L-amino acids"J. Biol. Chem.. 275. 9690-9698 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakajima, N, Sekine, T, Cha, S-H, Tojo, A, Hosoyamada, M, Kanai, Y, Yan, K, Awa, S, and Endou, H: "Developmental changes in multispecific organic anion transporter 1 expression in the rat kidney"Kidney Int.. 57. 1608-1616 (2000)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2001-10-23  

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