Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors
Abstract
We have obtained, for the first time, a quantitative protein expression profile of membrane transporters and receptors in human brain microvessels, that is, the blood-brain barrier (BBB). Brain microvessels were isolated from brain cortexes of seven males (16-77 years old) and protein expression of 114 membrane proteins was determined by means of a liquid chromatography-tandem mass spectrometric quantification method using recently established in-silico peptide selection criteria. Among drug transporters, breast cancer resistance protein showed the most abundant protein expression (8.14 fmol/μg protein), and its expression level was 1.85-fold greater in humans than in mice. By contrast, the expression level of P-glycoprotein in humans (6.06 fmol/μg protein) was 2.33-fold smaller than that of mdr1a in mice. The organic anion transporters reported in rodent BBB, that is, multidrug resistance-associated protein, organic anion transporter and organic anion-transporting polypeptide family members, were under limit of quantification in humans, except multidrug resistance-associated protein 4 (0.195 fmol/μg protein). Among detected transporters and receptors for endogenous substances, the glucose transporter 1 level was similar to that of mouse, while the L-type amino acid transporter 1 level was fivefold smaller than that of mouse. These findings should be useful for understanding human BBB function and its differences from that in mouse.
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Comparison of 114 endothelial proteins between mice and humans revealed striking differences in expression; ABCG2 exhibited greater expression in humans, whereas LAT1, MCT1, TfR, ABCB1, and MRP4 exhibited greater expression in mice.
“Interestingly, comparison of 114 endothelial proteins between mice and humans revealed some striking differences in expression; for example, the active efflux ABCG2 transporter exhibited greater expression in humans, whereas LAT1 and MCT1 CMTs, TfR RMT, and ABCB1 and MRP4 active efflux transporters exhibited greater expression in mice (602).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [602]
Oatp1c1 is highly expressed in endothelial cells of the rodent BBB, but not the human BBB.
“Oatp1c1 is highly expressed in endothelial cells of the rodent BBB (Roberts et al., 2008), but not the human BBB (Uchida et al., 2011)”
From Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier (2017) · cites this paper as Uchida et al., 2011
TfR is expressed at high levels at the blood-brain barrier due to its physiological function to deliver iron to the brain.
“As the TfR is expressed at high levels at the blood–brain barrier [106,107] due to its physiological function to deliver iron to the brain, it is one of the most studied molecules for receptor-mediated drug delivery to the brain.”
From Iron as a central player and promising target in cancer progression (2019) · cites this paper as [107]
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- Authors
- Uchida, Y., Ohtsuki, S., Katsukura, Y., Ikeda, C., Suzuki, T., Kamiie, J., & Terasaki, T.
- Affiliations
- Tohoku University (JP)
- Azabu University (JP)
- Corresponding author
- Terasaki, Tetsuya
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2011-02-25
- Volume
- 117
- Issue
- 2
- Pages
- 333-345
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2136487679
- Cited by
- 881
- References
- 58
- Citations by year
- 2026: 32 · 2025: 36 · 2024: 87 · 2023: 54 · 2022: 70 · 2021: 73 · 2020: 73 · 2019: 55 · 2018: 60 · 2017: 52 · 2016: 41 · 2015: 65 · 2014: 62 · 2013: 58 · 2012: 45
- FWCI
- 31.90
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (23790170)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- blood-brain barrier, cerebral microvasculature, membrane transporters, cell surface receptors, protein expression profiling, ABCG2, P-glycoprotein, MRP4, organic anion transporters, organic anion transporting polypeptides, glucose transporter 1, LAT1
- MeSH terms
- Adolescent, Adult, Age Factors, Aged, Animals, Biological Transport, Blood-Brain Barrier, Brain, Chromatography, Liquid, Humans, Male, Membrane Proteins, Middle Aged, Receptors, Cell Surface, Membrane Transport Proteins, Proteomics, Mice, Tandem Mass Spectrometry, Young Adult
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