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The 4F2hc/LAT1 complex transports l-DOPA across the blood–brain barrier
Abstract
L-DOPA is transported across the blood-brain barrier (BBB) by an amino acid transporter, system L. Recently, it has been demonstrated that system L consists of two subunits, 4F2hc and either LAT1 or LAT2. 4F2hc/LAT1 and 4F2hc/LAT2 show different transport characteristics, while their distribution in the brain has not been determined. To clarify whether 4F2hc/LAT1 participates in L-DOPA transport across the BBB, we first examined the expression of 4F2hc/LAT1 in the mouse brain capillary endothelial cell line, MBEC4, as an in vitro BBB model. Northern hybridization and immunoblotting revealed that both 4F2hc and LAT1 are expressed and form a heterodimer in MBEC4 cells. To confirm whether 4F2hc/LAT1 acts as system L to transport L-DOPA, we characterized L-DOPA uptake into the cells. The uptake process was time-dependent, temperature-sensitive, and Na(+)-independent. Neutral amino acids with bulky side chains and a bicyclic amino acid, 2-aminobicyclo-[2, 2,1]-heptane-2-carboxylic acid (BCH), inhibited L-DOPA uptake into MBEC4 cells to a great extent, while an acidic amino acid, basic amino acids, and glycine had no effect. Other neutral amino acids, such as alanine, asparagine, glutamine, serine, and threonine inhibited L-DOPA uptake by 40-70% at most. These characteristics are more compatible with those of 4F2hc/LAT1, rather than those of 4F2hc/LAT2. Finally, immunohistochemistry with anti-LAT1 antibody demonstrated that LAT1 is predominantly expressed in the microvessels of the…
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“Specifically, l-DOPA can be recognized by the large neutral amino acids transporter 1 on endothelial cells and be transported across the BBB for the treatment of Parkinson’s disease29–31.”
From Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system (2025) · cites this paper as [30]
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Self-citationAmino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family
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Metadata
- Authors
- Kageyama, T., Nakamura, M., Matsuo, A., Yamasaki, Y., Takakura, Y., Hashida, M., Kanai, Y., Naito, M., Tsuruo, T., Minato, N., & Shimohama, S.
- Affiliations
- Kyoto University (JP)
- Kyorin University (JP)
- Institute for Quantitative Biosciences, The University of Tokyo (JP)
- Corresponding author
- Shimohama, Shun
- ORCID
- Venue
- Brain Research
- Publisher
- Elsevier BV
- Published
- 2000-10
- Volume
- 879
- Issue
- 1-2
- Pages
- 115-121
- ISSN
- 0006-8993 (ISSN-L)
- OpenAlex
- W2152525754
- Cited by
- 298
- References
- 37
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 12 · 2023: 18 · 2022: 28 · 2021: 17 · 2020: 19 · 2019: 15 · 2018: 17 · 2017: 13 · 2016: 12 · 2015: 9 · 2014: 10 · 2013: 15 · 2012: 7
- FWCI
- 3.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- blood-brain barrier, LAT1, LAT2, system L amino acid transporter, amino acid transport, 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid
- MeSH terms
- Amino Acids, Animals, Biological Transport, Blood-Brain Barrier, Brain, Capillaries, Carrier Proteins, Cell Line, Cerebrovascular Circulation, Endothelium, Vascular, Female, Levodopa, Male, Mice, Inbred BALB C, Recombinant Proteins, Antigens, CD, Protein Subunits, Amino Acid Transport Systems, Fusion Regulatory Protein-1, Mice
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