title: ATP-binding Cassette Subfamily C Member 5 (ABCC5) Functions as an Efflux Transporter of Glutamate Conjugates and Analogs.
abstract: The ubiquitous efflux transporter ABCC5 (ATP-binding cassette subfamily C member 5) is present at high levels in the blood-brain barrier, neurons, and glia, but its in vivo substrates and function are not known. Using untargeted metabolomic screens, we show that Abcc5(-/-) mice accumulate endogenous glutamate conjugates in several tissues, but brain in particular. The abundant neurotransmitter N-acetylaspartylglutamate was 2.4-fold higher in Abcc5(-/-) brain. The metabolites that accumulated in Abcc5(-/-) tissues were depleted in cultured cells that overexpressed human ABCC5. In a vesicular membrane transport assay, ABCC5 also transported exogenous glutamate analogs, like the classic excitotoxic neurotoxins kainic acid, domoic acid, and NMDA; the therapeutic glutamate analog ZJ43; and, as previously shown, the anti-cancer drug methotrexate. Glutamate conjugates and analogs are of physiological relevance because they can affect the function of glutamate, the principal excitatory neurotransmitter in the brain. After CO2 asphyxiation, several immediate early genes were expressed at lower levels in Abcc5(-/-) brains than in wild type brains, suggesting altered glutamate signaling. Our results show that ABCC5 is a general glutamate conjugate and analog transporter that affects the disposition of endogenous metabolites, toxins, and drugs.
authors.affiliation: From the Division of Molecular Oncology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Jansen
authors.affiliation: From the Division of Molecular Oncology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Sunny
authors.initials: S
authors.lastname: Mahakena
authors.affiliation: From the Division of Molecular Oncology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: de Haas
authors.affiliation: From the Division of Molecular Oncology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Piet
authors.initials: P
authors.lastname: Borst
authors.affiliation: From the Division of Molecular Oncology, Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands k.vd.wetering@nki.nl.
authors.forename: Koen
authors.initials: K
authors.lastname: van de Wetering
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D004151:Dipeptides / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D014508:Urea / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D004151:Dipeptides; D007608:Kainic Acid; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009419:Nerve Tissue Proteins; D014508:Urea; C120809:ABCC5 protein, human; C492376:Abcc5 protein, mouse; C486211:ZJ43; C027172:isospaglumic acid; C012301:domoic acid
keywords: MRP5; blood-brain barrier; brain; drug transport; glutamate; neurotoxin; neurotransmitter transport