ATP-binding Cassette Sub-family C Member 5 (ABCC5) Functions as an Efflux Transporter of Glutamate Conjugates and Analogs

ABSTRACT: The ubiquitous efflux transporter ATP-binding cassette sub-family C member 5 (ABCC5) is present at high levels in the blood-brain barrier, neurons and glia, but its function is not known. Untargeted metabolomic screens revealed that Abcc5-/- mice accumulate endogenous glutamate conjugates in several tissues, but brain in particular. The abundant neurotransmitter N-acetylaspartylglutamate (NAAG), for example, was over 2-fold higher in Abcc5-/- brain. In line with ABCC5-mediated transport, the metabolites that accumulated in Abcc5-/- tissues were depleted in cultured cells that overexpressed human ABCC5. Using membrane vesicles, we show that ABCC5 not only transports the metabolites detected in our screen, but also a wide range of peptides containing a C-terminal glutamate. Glutamate conjugates are of physiological relevance because they can affect the function of glutamate, the principal excitatory neurotransmitter in the brain. Interestingly, we found that ABCC5 also transports exogenous glutamate analogs, like the classic excitotoxic neurotoxins kainic acid, domoic acid and N-methyl-D-aspartate (NMDA), and the therapeutic glutamate analog ZJ43. Taken together, we have identified ABCC5 as a general glutamate conjugate and analog transporter that can affect the disposition of endogenous metabolites, toxins and drugs.

OTHER RELATED OMICS DATASETS IN: PRJNA283238

INSTRUMENT(S): LTQ Orbitrap Discovery (Thermo Scientific)

PROVIDER: MTBLS197 | MetaboLights | 2015-11-02

REPOSITORIES: MetaboLights