The Expression and Function of ABC Transporters at the Blood-Brain Barrier

Dore‐Duffy, Paula; Esen, Nilufer; Serkin, Zakhar

doi:10.1201/b18606-8

Cited by 4 publications

(18 citation statements)

References 282 publications

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“…ATP-binding cassette (ABC) transporters comprise a superfamily of transmembrane proteins that are conserved in evolution and found in many species from prokaryotes to humans [ 1 , 2 , 3 ]. Functional transporter proteins typically contain one or two ATP-binding domains (also known as nucleotide-binding domain (NBD)) and transmembrane (TM) domains.…”

Section: Introductionmentioning

confidence: 99%

“…Functional transporter proteins typically contain one or two ATP-binding domains (also known as nucleotide-binding domain (NBD)) and transmembrane (TM) domains. Each TM domain contains six membrane-spanning alpha-helices and determines specificity for substrates [ 1 , 2 , 3 ]. Eukaryotic ABC transporters are either full transporters containing two NBDs and two TM domains or half transporters with one NBD and one TM domain.…”

Section: Introductionmentioning

confidence: 99%

“…ABC transporters are widely expressed in different tissues and carry out important physiological functions through the transport of metabolites, ions, lipids/cholesterol/steroids, drugs/xenobiotics, antibiotics, toxins and peptides across biological membranes (known functions of ABC transporters are listed in Supplementary Table S1 ). Notably, ABCB1/MDR-1 (multidrug resistance 1) P-glycoprotein (ABCB1/Pgp), ABCG2/breast cancer resistant protein (ABCG2/BCRP) and ABCC subfamily members/multidrug resistant proteins (ABCC1-5/MRP1-5) play critical roles in drug efflux transport and in forming barrier functions in the human body, including the blood–brain barrier (BBB), blood-cerebrospinal fluid barrier (BCSFB), blood-retinal barrier, blood-testis barrier and placenta barrier [ 3 , 6 , 7 , 8 , 9 , 10 ]. These barriers protect organs and tissues from blood-borne toxic substances and metabolic waste.…”

Section: Introductionmentioning

confidence: 99%

“…These barriers protect organs and tissues from blood-borne toxic substances and metabolic waste. However, they can also impede the delivery of therapeutics into ‘protected’ organs and cells; for example, the BBB-expressed ABC transporters actively extrude substrate drugs, making them inaccessible to the targets in the central nervous system (CNS) [ 3 , 11 , 12 , 13 ]. The expression and function of ABC transporters are regulated by a spectrum of endogenous and exogenous factors, including nuclear receptors, xenobiotics/drugs and a variety of inflammatory molecules [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…The expression and function of ABC transporters are regulated by a spectrum of endogenous and exogenous factors, including nuclear receptors, xenobiotics/drugs and a variety of inflammatory molecules [ 12 ]. Long-term administrations of certain xenobiotics/drugs, such as chemotherapeutic and epilepsy drugs, can up-regulate the expression of ABC drug transporters, leading to multidrug-resistant (MDR) phenotypes, particularly in cancer chemotherapy and at the BBB [ 3 , 12 ]. The mutations in ABC transporter genes resulting in disease phenotypes have been described previously [ 2 , 3 ] ( Table S1 ).…”

Section: Introductionmentioning

confidence: 99%

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Differential Expression of ABC Transporter Genes in Brain Vessels vs. Peripheral Tissues and Vessels from Human, Mouse and Rat

et al. 2023

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Background: ATP-binding cassette (ABC) transporters comprise a superfamily of genes encoding membrane proteins with nucleotide-binding domains (NBD). These transporters, including drug efflux across the blood–brain barrier (BBB), carry a variety of substrates through plasma membranes against substrate gradients, fueled by hydrolyzing ATP. The expression patterns/enrichment of ABC transporter genes in brain microvessels compared to peripheral vessels and tissues are largely uncharacterized. Methods: In this study, the expression patterns of ABC transporter genes in brain microvessels, peripheral tissues (lung, liver and spleen) and lung vessels were investigated using RNA-seq and WesTM analyses in three species: human, mouse and rat. Results: The study demonstrated that ABC drug efflux transporter genes (including ABCB1, ABCG2, ABCC4 and ABCC5) were highly expressed in isolated brain microvessels in all three species studied; the expression of ABCB1, ABCG2, ABCC1, ABCC4 and ABCC5 was generally higher in rodent brain microvessels compared to those of humans. In contrast, ABCC2 and ABCC3 expression was low in brain microvessels, but high in rodent liver and lung vessels. Overall, most ABC transporters (with the exception of drug efflux transporters) were enriched in peripheral tissues compared to brain microvessels in humans, while in rodent species, additional ABC transporters were found to be enriched in brain microvessels. Conclusions: This study furthers the understanding of species similarities and differences in the expression patterns of ABC transporter genes; this is important for translational studies in drug development. In particular, CNS drug delivery and toxicity may vary among species depending on their unique profiles of ABC transporter expression in brain microvessels and BBB.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential Expression of ABC Transporter Genes in Brain Vessels vs. Peripheral Tissues and Vessels from Human, Mouse and Rat

et al. 2023

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Blood-Brain Barrier (BBB)-Crossing Strategies for Improved Treatment of CNS Disorders

Zhang

2023

Handbook of Experimental Pharmacology

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The proteome of the blood–brain barrier in rat and mouse: highly specific identification of proteins on the luminal surface of brain microvessels by in vivo glycocapture

Tremblay,

Alata,

Slinn

et al. 2024

Fluids Barriers CNS

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Background The active transport of molecules into the brain from blood is regulated by receptors, transporters, and other cell surface proteins that are present on the luminal surface of endothelial cells at the blood–brain barrier (BBB). However, proteomic profiling of proteins present on the luminal endothelial cell surface of the BBB has proven challenging due to difficulty in labelling these proteins in a way that allows efficient purification of these relatively low abundance cell surface proteins. Methods Here we describe a novel perfusion-based labelling workflow: in vivo glycocapture. This workflow relies on the oxidation of glycans present on the luminal vessel surface via perfusion of a mild oxidizing agent, followed by subsequent isolation of glycoproteins by covalent linkage of their oxidized glycans to hydrazide beads. Mass spectrometry-based identification of the isolated proteins enables high-confidence identification of endothelial cell surface proteins in rats and mice. Results Using the developed workflow, 347 proteins were identified from the BBB in rat and 224 proteins in mouse, for a total of 395 proteins in both species combined. These proteins included many proteins with transporter activity (73 proteins), cell adhesion proteins (47 proteins), and transmembrane signal receptors (31 proteins). To identify proteins that are enriched in vessels relative to the entire brain, we established a vessel-enrichment score and showed that proteins with a high vessel-enrichment score are involved in vascular development functions, binding to integrins, and cell adhesion. Using publicly-available single-cell RNAseq data, we show that the proteins identified by in vivo glycocapture were more likely to be detected by scRNAseq in endothelial cells than in any other cell type. Furthermore, nearly 50% of the genes encoding cell-surface proteins that were detected by scRNAseq in endothelial cells were also identified by in vivo glycocapture. Conclusions The proteins identified by in vivo glycocapture in this work represent the most complete and specific profiling of proteins on the luminal BBB surface to date. The identified proteins reflect possible targets for the development of antibodies to improve the crossing of therapeutic proteins into the brain and will contribute to our further understanding of BBB transport mechanisms.

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The Expression and Function of ABC Transporters at the Blood-Brain Barrier

Cited by 4 publications

References 282 publications

Differential Expression of ABC Transporter Genes in Brain Vessels vs. Peripheral Tissues and Vessels from Human, Mouse and Rat

Differential Expression of ABC Transporter Genes in Brain Vessels vs. Peripheral Tissues and Vessels from Human, Mouse and Rat

Blood-Brain Barrier (BBB)-Crossing Strategies for Improved Treatment of CNS Disorders

The proteome of the blood–brain barrier in rat and mouse: highly specific identification of proteins on the luminal surface of brain microvessels by in vivo glycocapture

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