PMID:19295159

Citation	Mayer, F, Mayer, N, Chinn, L, Pinsonneault, RL, Kroetz, D and Bainton, RJ (2009) Evolutionary conservation of vertebrate blood-brain barrier chemoprotective mechanisms in Drosophila. J. Neurosci. 29:3538-50
Abstract	Pharmacologic remedy of many brain diseases is difficult because of the powerful drug exclusion properties of the blood-brain barrier (BBB). Chemical isolation of the vertebrate brain is achieved through the highly integrated, anatomically compact and functionally overlapping chemical isolation processes of the BBB. These include functions that need to be coordinated between tight diffusion junctions and unidirectionally acting xenobiotic transporters. Understanding of many of these processes has been hampered, because they are not well mimicked by ex vivo models of the BBB and have been experimentally difficult and expensive to disentangle in intact rodent models. Here we show that the Drosophila melanogaster (Dm) humoral/CNS barrier conserves the xenobiotic exclusion properties found in the vertebrate vascular endothelium. We characterize a fly ATP binding cassette (ABC) transporter, Mdr65, that functions similarly to mammalian xenobiotic BBB transporters and show that varying its levels solely in the Dm BBB changes the inherent sensitivity of the barrier to cytotoxic pharmaceuticals. Furthermore, we demonstrate orthologous function between Mdr65 and vertebrate ABC transporters by rescuing chemical protection of the Dm brain with human MDR1/Pgp. These data indicate that the ancient origins of CNS chemoprotection extend to both conserved molecular means and functionally analogous anatomic spaces that together promote CNS selective drug partition. Thus, Dm presents an experimentally tractable system for analyzing physiological properties of the BBB in an intact organism.
Links	PubMed PMC3040577 Online version:10.1523/JNEUROSCI.5564-08.2009
Keywords	ATP-Binding Cassette Transporters/genetics; ATP-Binding Cassette Transporters/metabolism; Animals; Animals, Genetically Modified; Blood-Brain Barrier/drug effects; Blood-Brain Barrier/metabolism; Cell Line; Drosophila Proteins/genetics; Drosophila Proteins/metabolism; Drosophila melanogaster/genetics; Drosophila melanogaster/physiology; Drug Delivery Systems; Evolution, Molecular; Humans; Neuroprotective Agents/metabolism; P-Glycoprotein/metabolism; P-Glycoproteins/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
DROME:MDR65	enables	GO:0008559: ABC-type xenobiotic transporter activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
DROME:MDR65	involved_in	GO:0042908: xenobiotic transport	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
DROME:MDR65	enables	GO:0015562: efflux transmembrane transporter activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
DROME:MDR65	part_of	GO:0043190: ATP-binding cassette (ABC) transporter complex	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
DROME:MDR65	located_in	GO:0005919: pleated septate junction	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
DROME:MDR65	involved_in	GO:0060857: establishment of glial blood-brain barrier	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
DROME:MOODY	located_in	GO:0005919: pleated septate junction	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete

References

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