Amino acid transceptors: gate keepers of nutrient exchange and regulators of nutrient signaling

Abstract

Amino acid transporters at the surface of cells are in an ideal location to relay nutritional information, as well as nutrients themselves, to the cell interior. These transporters are able to modulate signaling downstream of intracellular amino acid receptors by regulating intracellular amino acid concentrations through processes of coupled transport. The concept of dual-function amino acid transporter/receptor (or "transceptor") proteins is well established in primitive eukaryotes such as yeast, where detection of extracellular amino acid deficiency leads to upregulation of proteins involved in biosynthesis and transport of the deficient amino acid(s). The evolution of the "extracellular milieu" and nutrient-regulated endocrine controls in higher eukaryotes, alongside their frequent inability to synthesize all proteinaceous amino acids (and, hence, the requirement for indispensable amino acids in their diet), appears to have lessened the priority of extracellular amino acid sensing as a stimulus for metabolic signals. Nevertheless, recent studies of amino acid transporters in flies and mammalian cell lines have revealed perhaps unanticipated "echoes" of these transceptor functions, which are revealed by cellular stresses (notably starvation) or gene modification/silencing. APC-transporter superfamily members, including slimfast, path, and SNAT2 all appear capable of sensing and signaling amino acid availability to the target of rapamycin (TOR) pathway, possibly through PI 3-kinase-dependent mechanisms. We hypothesize (by extrapolation from knowledge of the yeast Ssy1 transceptor) that, at least for SNAT2, the transceptor discriminates between extracellular and intracellular amino acid stimuli when evoking a signal.

Fig. 1.

Schematic diagram showing processes that contribute to free amino acid (AA) turnover in animal cells. Note that AA transporters contribute to both influx and efflux of AAs at the cell surface. This review considers the evidence for both extracellular and intracellular amino acid “receptors” upstream of nutrient-responsive signaling mechanisms involved in control of cellular processes. PS, protein synthesis; PB, protein breakdown.

Fig. 2.

Integration of primary (I), secondary (II), and tertiary (III) active transport (AT) mechanisms may affect transmembrane distribution of particular AAs. Secondary active transporters (e.g., System A/SNAT2) generate net movement of AA from the extracellular to the intracellular pool, whereas tertiary active transport through exchangers such as LAT1 (System L) allows for redistribution of individual AAs without affecting total pool sizes.

Fig. 3.

Generalized schema of possible interactions between AA transporters/transceptors and major nutrient-responsive signaling pathways in animal cells [target of rapamycin complex 1 (TORC1), general control nonrepressed (GCN)2 pathways]. ATF, activating transcription factor. For clarity, transporter and transceptor functions are shown separately, but it should be stressed that both are incorporated within a true AA transceptor (e.g., Gap1, SNAT2). Transceptors are proposed to exist in both signaling and nonsignaling states: In the diagram, State 1 (AA bound at extracellular surface) is stimulatory, or ON, whereas State 2 (AA bound at intracellular surface) is inhibitory, or OFF, with respect to the TORC1 pathway. This may account for transient activation of the TOR pathway by external methyl-aminoisobutyric acid (Me-AIB) before it accumulates substantially in the cytoplasm. Binding of any AA substrate (for SNAT2 at least) represses the adaptive upregulation of transporter/transceptor expression in response to nutrient deprivation, although whether this requires intracellular or extracellular binding remains a matter of debate. AA transporters may modulate intracellular free AA pools by coupled transport processes at the cell surface, including primary (I), secondary (II), and tertiary (III) active transport (as detailed in Fig. 2). In discrete, unperfused extracellular spaces (e.g., synaptic clefts), AA transporter actions may also exert significant effects on extracellular AA pools.