Amino acid availability regulates cellular physiology by modulating gene expression and signal transduction pathways. However, although the signalling intermediates between nutrient availability and altered gene expression have become increasingly well documented, how eukaryotic cells sense the presence of either a nutritionally rich or deprived medium is still uncertain. From recent studies it appears that the intracellular amino acid pool size is particularly important in regulating translational effectors, thus, regulated transport of amino acids across the plasma membrane represents a means by which the cellular response to amino acids could be controlled. Furthermore, evidence from studies with transportable amino acid analogues has demonstrated that flux through amino acid transporters may act as an initiator of nutritional signalling. This evidence, coupled with the substrate selectivity and sensitivity to nutrient availability classically associated with amino acid transporters, plus the recent discovery of transporter-associated signalling proteins, demonstrates a potential role for nutrient transporters as initiators of cellular nutrient signalling. Here, we review the evidence supporting the idea that distinct amino acid “receptors” function to detect and transmit certain nutrient stimuli in higher eukaryotes. In particular, we focus on the role that amino acid transporters may play in the sensing of amino acid levels, both directly as initiators of nutrient signalling and indirectly as regulators of external amino acid access to intracellular receptor/signalling mechanisms.

Abbreviations used: eIF, eukaryotic initiation factor; 4E-BP, eIF4E-binding protein; AIB, α-aminoisobutyric acid; ALS, amyotrophic lateral sclerosis; AMPK, AMP-activated protein kinase; APC, amino acid–polyamine–choline; CaR, calcium receptor; CAT, cationic amino acid transporter; CHO, Chinese-hamster ovary; DAT, dopamine transporter; EAAT, excitatory amino acid transporter; GABA, γ-aminobutyric acid; GAT, GABA transporter; GCN, general control; GLYT, glycine transporter; GTRAP, glutamate-transporter-associated protein; Hic-5, hydrogen peroxide-inducible clone-5; HSP, heat-shock protein; JNK, c-Jun N-terminal kinase; LAT, System L amino acid transporter; Leu8-MAP, Leu8-Lys4-Lys2-Lys-βAla; LIM, Lin-11, Isl-1 and Mec-3; MAP, microtubule-associated protein; MAPK, mitogen-activated protein kinase; Me-AIB, α-methylaminoisobutyric acid; (e)NOS, (endothelial) nitric oxide synthase; PFK1, 6-phosphofructo-1-kinase; PFK2, 6-phosphofructo-2-kinase; SH3, Src homology 3; S6K, ribosomal protein S6 kinase; SAT, System A transporter; SLC, solute carrier; (m)TOR, (mammalian) target of rapamycin; VGLUT, vesicular glutamate transporter.

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