Unconventional Functions of Amino Acid Transporters: Role in Macropinocytosis (SLC38A5/SLC38A3) and Diet-Induced Obesity/Metabolic Syndrome (SLC6A19/SLC6A14/SLC6A6)

Abstract

Amino acid transporters are expressed in mammalian cells not only in the plasma membrane but also in intracellular membranes. The conventional function of these transporters is to transfer their amino acid substrates across the lipid bilayer; the direction of the transfer is dictated by the combined gradients for the amino acid substrates and the co-transported ions (Na+, H+, K+ or Cl−) across the membrane. In cases of electrogenic transporters, the membrane potential also contributes to the direction of the amino acid transfer. In addition to this expected traditional function, several unconventional functions are known for some of these amino acid transporters. This includes their role in intracellular signaling, regulation of acid–base balance, and entry of viruses into cells. Such functions expand the biological roles of these transporters beyond the logical amino acid homeostasis. In recent years, two additional unconventional biochemical/metabolic processes regulated by certain amino acid transporters have come to be recognized: macropinocytosis and obesity. This adds to the repertoire of biological processes that are controlled and regulated by amino acid transporters in health and disease. In the present review, we highlight the unusual involvement of selective amino acid transporters in macropinocytosis (SLC38A5/SLC38A3) and diet-induced obesity/metabolic syndrome (SLC6A19/SLC6A14/SLC6A6).

Induction of Oxidative Stress and Ferroptosis in Triple-Negative Breast Cancer Cells by Niclosamide via Blockade of the Function and Expression of SLC38A5 and SLC7A11

“…Its transport function as an amino acid-dependent Na + /H + exchanger couples amino acid entry into cells via this transporter to intracellular alkalinization, which promotes macropinocytosis. Since SLC38A3 functions in an identical manner in terms of transport modality, we have postulated that this transporter might also promote micropinocytosis, even though it is only speculative at this time and has not yet been validated experimentally [ 19 ]. In the present study, we have uncovered another important functional feature of SLC38A5 in TNBC.…”

“…It is upregulated in TNBC [ 15 ] and pancreatic cancer [ 16 , 17 ]. In addition to mediating the uptake of amino acids, SLC38A5 also promotes macropinocytosis, a special form of nutrient uptake in cancer cells [ 15 , 18 , 19 ]. In the present study with TNBC cells, we explored the possibility that SLC38A5 could transport seleno-methionine (Se-Met), the most predominant dietary source of selenium.…”

Identification of Key Genes and Biological Pathways in Bipolar Disorder by Bioinformatics and Next Generation Sequencing Data Analysis

“…S100A12 [381], SLC6A19 [382], TXN (thioredoxin) [383], TLR9 [384], S100P [385], S100A9 [386], ANK1 [387], CA1 [388], HP (haptoglobin) [389], ARG1 [390], SNCA (synuclein alpha) [391], STARD10 [392], PINK1 [393], TFR2 [394], B2M [395], PHOSPHO1 [396], CBS (cystathionine beta-synthase) [397], WNT6 [398], NFE2 [399], RNF10 [400], CARM1 [401], GLRX5 [402], PPP2R5B [403], GPX1 [404], FOXO4 [405], ARHGEF12 [406], FOXA1 [407], PAX4 [351], ABCG8 [408], RARRES2 [409], NOX1 [410], CPE (carboxypeptidase E) [411], IL33 [412], ADAMTS7 [413], SFTPB (surfactant protein B) [255], MGP (matrix Gla protein) [257], VTN (vitronectin) [414], PRSS1 [415], GHR (growth hormone receptor) [416], ERBB3 [417], GFAP (glial fibrillary acidic protein) [418], CD34 [419], MSTN (myostatin) [420], NOTCH3 [421], NR5A2 [422], SMOC1 [423], GNB3 [424], CTNNA3 [425], SFRP5 [283], GDF15 [285], AXL (AXL receptor tyrosine kinase) [426], CAV1 [427], LCT (lactase) [428], FZD4 [429], KCNMA1 [430], FMOD (fibromodulin) [431] and CPA6 [432] were revealed to be correlated with disease outcome in patients with diabetes mellitus. Previous studies have demonstrated that SLC6A19 [433], DNAJC6 [434], TXN (thioredoxin) [383], S100A9 [435], HP (haptoglobin) [436], ARG1 [437], SNCA (synuclein alpha) [391], CEP19 [438], CAMP (cathelicidin antimicrobial peptide) [439], PINK1 [440], UBB (ubiquitin B) [441], PHOSPHO1 [396], CBS (cystathionine beta-synthase) [397], PPP2R5B...…”

Impact of Oncogenic Changes in p53 and KRAS on Macropinocytosis and Ferroptosis in Colon Cancer Cells and Anticancer Efficacy of Niclosamide with Differential Effects on These Two Processes

“…Recently, we found that the amino acid transporter SLC38A5, which functions as an amino acid-dependent Na + /H + exchanger, is also able to induce macropinocytosis in breast cancer cells [43]. SLC38A3, another amino acid transporter that functions similar to SLC38A5, may also affect macropinocytosis [44], but this has not yet been investigated experimentally. In the present study, we examined the influence of p53 and KRAS mutation on the expression and function of SLC38A3 and SLC38A5 by RT-PCR and transport function.…”