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The solute carrier transporters and the brain: Physiological and pharmacological implications - PubMed

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The solute carrier transporters and the brain: Physiological and pharmacological implications

Chengliang Hu et al. Asian J Pharm Sci. 2020 Mar.

Abstract

Solute carriers (SLCs) are the largest family of transmembrane transporters that determine the exchange of various substances, including nutrients, ions, metabolites, and drugs across biological membranes. To date, the presence of about 287 SLC genes have been identified in the brain, among which mutations or the resultant dysfunctions of 71 SLC genes have been reported to be correlated with human brain disorders. Although increasing interest in SLCs have focused on drug development, SLCs are currently still under-explored as drug targets, especially in the brain. We summarize the main substrates and functions of SLCs that are expressed in the brain, with an emphasis on selected SLCs that are important physiologically, pathologically, and pharmacologically in the blood-brain barrier, astrocytes, and neurons. Evidence suggests that a fraction of SLCs are regulated along with the occurrences of brain disorders, among which epilepsy, neurodegenerative diseases, and autism are representative. Given the review of SLCs involved in the onset and procession of brain disorders, we hope these SLCs will be screened as promising drug targets to improve drug delivery to the brain.

Keywords: Blood-brain barrier; Brain disorder; Drug; Solute carrier transporter.

© 2019 Shenyang Pharmaceutical University. Published by Elsevier B.V.

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Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

Image, graphical abstract
Graphical abstract
Fig 1
Fig. 1

The main solute carrier transporters involved in glutamate/GABA-glutamine cycle. Glutamate is packaged into synaptic vesicles in pre-synaptic neurons by SLC17A6/A7. After release into the synaptic cleft and stimulating post-synaptic neurons, the signal is terminated by astroglial uptake of glutamate via SLC1A2/A3. Glutamate is converted to glutamine via glutamine synthase (GS). Glutamine is transported out of astrocytes through SLC38A3/A5, shuttled to neurons via SLC38A2/A7/SLC1A5, and converted to glutamate by phosphate-activated glutaminase (PAG) to complete the glutamate–glutamine cycle. GABA is packaged into synaptic vesicles by SLC32A1 and released into the synaptic cleft. SLC6A11 and SLC6A1 are responsible for GABA uptake in astrocytes and neurons, respectively. GABA is metabolized to α-ketoglutarate (α-KG) via TCA cycle and then glutamate. The following steps are similar to the glutamatergic synapses until glutamate is converted to GABA by glutamate decarboxylase (GAD) in GABA-ergic neurons. GABA is repackaged in vesicles for further synaptic release.

Fig 2
Fig. 2

Examples of SLC mediated drug transport across the blood-brain barrier and in glioblastomas and neurons. Three strategies of SLC mediated drug transportation in the brain. 1. SLC7A5 mediated liposomal drug carrier system. (1) An

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-DOPA functionalized amphiphile is loaded with STAT3 inhibitor WP1066, a drug for the treatment of glioblastoma, and is modified with DSPE-(PEG)27–NH2, a reagent to enhance the circulation stability of the liposomes; (2) SLC7A5 mediates the uptake of Amphi-DOPA into the BBB endothelial cells; (3) Released Amphi-DOPA is recognized by SLC7A5 localized to the membrane of glioblastoma cells and is taken up by tumor cells; (4) WP1066 is released from the Amphi-DOPA and induces tumor cell death by inhibiting the STAT3 pathway. 2. SLC22A5 mediates the nanoparticle drug carrier system. (1)

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-carnitine-conjugated poly(lactic-co-glycolic acid) (PLGA, biodegradable synthetic polymer) nanoparticles (LC-PLGA NPs) are developed which are loaded with paclitaxel, an anti-glioma drug; (2) SLC22A5 mediates the uptake of LC-PLGA NPs into the BBB endothelial cells; (3) Released LC-PLGA NPs are recognized by SLC22A5 localized in the membrane of glioblastoma cells and are taken up by tumor cells; (4) paclitaxel is released from the LC-PLGA NPs, leading to inhibition of tumor cell proliferation and induction of apoptosis by the anti-microtubule effect. 3. SLC7A5 mediates prodrug carrier system.

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-DOPA is a prodrug of the neurotransmitters dopamine. It is transported across the BBB and taken up by neurons via SLC7A5.

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-DOPA is converted to dopamine for the treatment of Parkinson's disease.

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