SLC29A4 Membrane Protein Introduction

Introduction of SLC29A4

Solute carrier family 29 member 4 (SLC29A4), also known as Equilibrative nucleoside transporter 4 (ENT4), is a protein that in humans is encoded by the SLC29A4 gene. Belonging to the Equilibrative nucleoside transporter family, SLC29A4 also contains 11 transmembrane domains, several putative phosphorylation sites, and a C-terminal N-glycosylation site. SLC29A4 gene is mapped to chromosome 7p22.1. SLC29A4 is highly expressed in brain, heart (in both cardiomyocytes and vascular endothelial cells) and skeletal muscle and more weakly expressed in kidney, heart, and liver.

Function of SLC29A4 Membrane Protein

Unlike other ENT subtypes, SLC29A4 is not broadly specific for nucleosides and nucleoside analogs such as uridine, cytidine, thymidine, inosine, guanosine, and azidothymidine. However, it can transport adenosine efficiently with a fashion highly sensitive to extracellular pH, with maximal activity in the pH range 5.5 to 6.5. SLC29A4 activity is low at neutral pH but is greatly increased at acidic pH, showing pH-dependent adenosine transport activity. Notably, SLC29A4 has been shown to transport several compounds, such as monoamine neurotransmitters 1-methyl-4-phenylpyridinium and biogenic amines including serotonin, dopamine, norepinephrine, and epinephrine. So, it plays a significant role in regulating central nervous system homeostasis of monoamine neurotransmitters. In addition, it is reported that SLC29A4 is involved in luminal transport of organic cations in the kidney and seems to use luminal proton gradient to drive organic cation reabsorption.

Fig.1 Topological model of human ENT protein. (Sundaram, 2001)

Application SLC29A4 of Membrane Protein in Literature

1. Wang C., et al. Dipyridamole analogs as pharmacological inhibitors of equilibrative nucleoside transporters. Identification of novel potent and selective inhibitors of the adenosine transporter function of human equilibrative nucleoside transporter 4 (hENT4). Biochemical pharmacology. 2013, 86(11): 1531-1540. PubMed ID: 24021350
   
   

   This article identifies the most potent and selective inhibitors of hENT4 to date, which may serve as useful pharmacological/biochemical tools and/or potential leads for ENT4-based therapeutics.

2. Adamsen D., et al. Autism spectrum disorder associated with low serotonin in CSF and mutations in the SLC29A4 plasma membrane monoamine transporter (PMAT) gene. Molecular autism. 2014, 5(1): 43. PubMed ID: 25802735
   
   

   This article reveals SLC29A4 mutations are associated with autism spectrum disorder (ASD) population although not invariably to low brain serotonin. In addition, SLC29A4 dysfunction is speculated to raise serotonin prenatally, exerting a negative feedback inhibition through serotonin receptors on development of serotonin networks and local serotonin synthesis.

3. Yang C. and Leung G.P.H. Equilibrative Nucleoside Transporters 1 and 4: Which One Is a Better Target for Cardioprotection Against Ischemia-Reperfusion Injury? Journal of cardiovascular pharmacology. 2015, 65(6): 517. PubMed ID: 26070128
   
   

   This study concludes that ENT4 may contribute to the regulation of extracellular adenosine in the heart, especially under the acidotic conditions associated with ischemia, so the development of specific ENT4 inhibitors may open a new avenue in research on ischemic heart disease therapy.

4. Usui T., et al. Histamine elimination from the cerebrospinal fluid across the blood-cerebrospinal fluid barrier: involvement of plasma membrane monoamine transporter (PMAT/SLC29A4). Journal of neurochemistry. 2016, 139(3): 408-418. PubMed ID: 27501284
   
   

   The authors reveal that the inhibitors of plasma membrane monoamine transporter (PMAT/SLC29A4) can significantly inhibit the [³H]histamine uptake by TR-CSFB3 cells, suggesting the elimination of histamine from the CSF via PMAT/SLC29A4 at the blood-brain barrier and blood-CSF barrier (BCSFB).

5. Duan H. and Wang J. Impaired monoamine and organic cation uptake in choroid plexus in mice with targeted disruption of the plasma membrane monoamine transporter (Slc29a4) gene. Journal of Biological Chemistry. 2013, 288(5): 3535-3544. PubMed ID:
   
   

   This article demonstrates that PMAT/SLC29A4 is a major transporter for choroid plexus (CP) uptake of bioactive amines and xenobiotic cations. By removing its substrates from the CSF, PMAT/SLC29A4 may play an important role in protecting the brain from cationic neurotoxins and other potentially toxic organic cations.

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Reference

1. Sundaram M, et al. (2001). Topology of a human equilibrative, nitrobenzylthioinosine (NBMPR)-sensitive nucleoside transporter (hENT1) implicated in the cellular uptake of adenosine and anti-cancer drugs. Journal of Biological Chemistry. 276(48): 45270-45275.

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