Amino acid transporters: éminences grises of nutrient signalling mechanisms?

Nutrient signalling by the mTOR (mammalian target of rapamycin) pathway involves upstream sensing of free AA (amino acid) concentrations. Several AA-regulated kinases have recently been identified as putative intracellular AA sensors. Their activity will reflect the balance between AA flows through underlying mechanisms which together determine the size of the intracellular free AA pool. For indispensable AAs, these mechanisms are primarily (i) AA transport across the cell membrane, and (ii) protein synthesis/breakdown. The System L AA transporter is the primary conduit for cellular entry of indispensable neutral AAs (including leucine and phenylalanine) and potentially a key modulator of AA-sensitive mTOR signalling. Coupling of substrate flows through System L and other AA transporters (e.g. System A) may extend the scope for sensing nutrient abundance. Factors influencing AA transporter activity (e.g. hormones) may affect intracellular AA concentrations and hence indirectly mTOR pathway activity. Several AA transporters are themselves regulated by AA availability through 'adaptive regulation', which may help to adjust the gain of AA sensing. The substrate-binding sites of AA transporters are potentially direct sensors of AA availability at both faces of the cell surface, and there is growing evidence that AA transporters of the SNAT (sodium-coupled neutral AA transporter) and PAT (proton-assisted AA transporter) families may operate, at least under some circumstances, as transporter-like sensors (or 'transceptors') upstream of mTOR.