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

Yangzom D Bhutia,Vadivel Ganapathy,Sathish Sivaprakasam,Sabarish Ramachandran,Marilyn Mathew

doi:10.3390/biom12020235

Yangzom D Bhutia, Vadivel Ganapathy + Show 3 more

Open Access

https://doi.org/10.3390/biom12020235

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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).

Highlights

The conventional function of amino acid transporters in mammalian cells is in the maintenance of amino acid homeostasis
The transport process mediated by these amino acid transporters is either uniport or obligatory exchange
The direction of the amino acid transfer mediated by a given amino acid transporter is dictated by multiple factors: concentration gradients for amino acid substrates and co-transported ions as well as membrane potential

Summary

Introduction

The conventional function of amino acid transporters in mammalian cells is in the maintenance of amino acid homeostasis. Biomolecules 2022, 12, 235 transporters are not expressed exclusively in the plasma membrane [1,2,3,4]; they are found in intracellular membranes, in the lysosomal [5,6] and mitochondrial membranes [7] This makes sense because amino acid needs of cells are met by uptake from extracellular sources and by transfer from lysosomes following proteolysis in conjunction with autophagy, pinocytosis and macropinocytosis. SLC (solute carrier) gene families (1, 6, 7, 16, 17, 25, 36, 38, 43 and 66) along with four non-transporter proteins (SLC3A1/rBAT, SLC3A2/4F2hc/CD98, ACE2 and collectrin) that serve as chaperones for some of these transporters [1,2] Depending on their cell-type specific expression, they function in the cellular uptake of amino acids and in transcellular transfer of amino acids across the barrier structures such as the blood–. Loss-of-function mutations in many of these transporters cause specific genetic diseases (e.g., Hartnup disease, cystinuria) [8,9,10,11]

Unconventional Functions of Amino Acid Transporters

Transport

Obesity and SLC6A19

Significance of SLC6A19 and SLC6A14 to Obesity in Humans

Taurine and Its Transporter in Connection with Obesity

Conclusions