Glutamine transporters in mammalian cells and their functions in physiology and cancer

Abstract

The SLC (solute carrier)-type transporters (~400 in number) in mammalian cells consist of 52 distinct gene families, grouped solely based on the amino acid sequence (primary structure) of the transporter proteins and not on their transport function. Among them are the transporters for amino acids. Fourteen of them, capable of transporting glutamine across the plasma membrane, are found in four families: SLC1, SLC6, SLC7, and SLC38. However, it is generally thought that the members of the SLC38 family are the principal transporters for glutamine. Some of the glutamine transporters are obligatory exchangers whereas some function as active transporters in one direction. While most glutamine transporters mediate the influx of the amino acid into cells, some actually mediate the efflux of the amino acid out of the cells. Glutamine transporters play important roles in a variety of tissues, including the liver, brain, kidney, and placenta, as clearly evident from the biological and biochemical phenotypes resulting from the deletion of specific glutamine transporters in mice. Owing to the obligatory role of glutamine in growth and proliferation of tumor cells, there is increasing attention on glutamine transporters in cancer biology as potential drug targets for cancer treatment. Selective blockers of certain glutamine transporters might be effective in preventing the entry of glutamine and other important amino acids into tumor cells, thus essentially starving these cells to death. This could represent the beginning of a new era in the discovery of novel anticancer drugs with a previously unexplored mode of action. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

Keywords: Biological function; Cancer; Glutamine transporters; Knockout mouse; Mode of transport; Plasma membrane.

Fig. 1

Transport mode of SLC1A5. AA⁰, neutral amino acids (net charge of zero on the molecule).

Fig. 2. Transport modes of SLC6A14 (A) and SLC6A19 (B)

AA^0,+, neutral (net charge of zero on the molecule) and cationic (net positive charge on the molecule) amino acids; AA⁰, neutral amino acids (net charge of zero on the molecule).

Fig. 3

Transport modes of the glutamine transporters in SLC7 gene family. AA⁰, neutral amino acids (net charge of zero on the molecule); AA⁺, cationic amino acids (net positive charge on the molecule); CSSC, cystine (oxidized form of cysteine)

Fig. 4

Transport modes of the glutamine transporters in SLC38 gene family. AA⁰, neutral amino acids (net charge of zero on the molecule).