SLC7A8 Membrane Protein Introduction

Introduction of SLC7A8

SLC7A8, also known as large neutral amino acids transporter small subunit 2 (hLAT2), is a protein that transports large neutral amino acids such as leucine, phenylalanine, tryptophan and methionine. Notably, SLC7A8 sometimes can also transport some smaller amino acids. SLC7A8 belongs to the hetero(di)meric amino acid transporters (HATs) subgroup of SLC7 family, APC (amino acid-polyamine-organo cation) superfamily. SLC7A8 gene is mapped to the chromosome 14q11.2-q13 and contains 11 exons. The structure of SLC7A8 is characterized with twelve predicted transmembrane domains (12TM), the N and C termini intracytoplasmic with a conserved cysteine residue that is conserved in human 4F2 light chains. SLC7A8 is expressed in several human tissues, with the highest expression in kidney, especially in the epithelial cells of proximal tubules.

Function of SLC7A8 Membrane Protein

Similar to SLC7A5 (hLAT1), SLC7A8 functions as a heterodimer by covalent combination with a heavy subunit (4F2 cell-surface antigen heavy chain, 4F2hc) (syn. CD98) through a conserved disulfide bridge. The complex LAT2-4F2hc (SLC7A8-SLC3A2) can transport large branched and aromatic neutral amino acids, which is responsible for uptake of essential amino acids in crucial body districts. It is documented that SLC7A8 has higher affinity for L-phenylalanine, but shows lower affinity for glutamine and serine. In kidney, SLC7A8 has been reported to contribute to the renal reabsorption of neutral amino acids in the basolateral domain of epithelial proximal tubule cells and mediation the re-uptake into the blood stream. Moreover, SLC7A8 is also involved in the efflux step of transepithelial amino acid transport. SLC7A8 gene mutations block flow of amino acids, which is likely an inherited cause of age-related hearing loss. Defects in SLC7A8 gene are closely associated with lysinuric protein intolerance (LPI), which is a severe multisystem disorder characterized by protein-rich food intolerance with secondary urea cycle disorders. The upregulation of SLC7A8 can increase asymmetric dimethylarginine (ADMA) efflux, which may be a mechanism by which ammonia interferes with intra-astrocytic ADMA content and subsequently, NO synthesis in various cell types.

Fig.1 Diagram of the homologous recombination in Slc7a8 locus. (Guarch, 2018)

Application of SLC7A8 Membrane Protein in Literature

1. Milewski K., et al. Ammonia reduces intracellular asymmetric dimethylarginine in cultured astrocytes stimulating its y+ LAT2 carrier-mediated loss. International journal of molecular sciences. 2017, 18(11): 2308. PubMed ID: 29099056
   
   

   The authors demonstrated that upregulation of SLC7A8 can increase asymmetric dimethylarginine (ADMA) efflux, by which ammonia interferes with intra-astrocytic (and possibly intra-endothelial cell) ADMA content and nitric oxide (NO) synthesis in astrocytes.

2. Guarch M.E., et al. Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss. eLife. 2018, 7: e31511. PubMed ID: 29355479
   
   

   This article screened a cohort of age-related hearing loss (ARHL) patients and detected several variants in SLC7A8 (p.Val302Ile, p.Arg418His, p.Thr402Met and p.Val460Glu), supporting a causative role for SLC7A8 in ARHL.

3. Balthasar C., et al. Methylmercury uptake into BeWo cells depends on LAT2-4F2hc, a system L amino acid transporter. International journal of molecular sciences. 2017, 18(8): 1730. PubMed ID: 28786956
   
   

   The authors revealed that LAT2-4F2hc acted as system L⁺ transporter to transport mercury compound methylmercury (MeHg), and it contributed to the uptake of amino acids and MeHg primarily at the apical membrane of the trophoblast, explaining the delivery of mercury to fetal blood.

4. Tina E., et al. Expression profile of the amino acid transporters SLC7A5, SLC7A7, SLC7A8 and the enzyme TDO2 in basal cell carcinoma. British Journal of Dermatology. 2018. 180(1):130-140. PubMed ID: 29938775
   
   

   The authors studied the expression profiles in basal cell carcinoma (BCCs) to find the differences in tumour metabolism, mainly focusing on the SLC 7A5, SLC 7A7, SLC 7A8, and the enzyme TDO2. Results showed that SLC7A5, SLC7A8, and TDO2 were upregulated in BCCs compared to non-tumour skin.

5. Barollo S., et al. Overexpression of L-type amino acid transporter 1 (LAT1) and 2 (LAT2): novel markers of neuroendocrine tumors. PloS one. 2016, 11(5): e0156044. PubMed ID: 27224648
   
   

   The authors assessed LAT1 and LAT2 expression in various management of pheochromocytoma (PHEO) and medullary thyroid carcinoma samples and they provided experimental evidence that LAT1 and LAT2 were overexpressed in some NET cancers (such as PHEO or MTC), giving the molecular basis to explain the increase of the DOPA uptake seen in such tumor cells.

SLC7A8 Preparation Options

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Reference

1. Guarch M E, et al. (2018). Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss. eLife. 7, e31511.

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