Role of amino acid transporters in amino acid sensing

Abstract

Amino acid (AA) transporters may act as sensors, as well as carriers, of tissue nutrient supplies. This review considers recent advances in our understanding of the AA-sensing functions of AA transporters in both epithelial and nonepithelial cells. These transporters mediate AA exchanges between extracellular and intracellular fluid compartments, delivering substrates to intracellular AA sensors. AA transporters on endosomal (eg, lysosomal) membranes may themselves function as intracellular AA sensors. AA transporters at the cell surface, particularly those for large neutral AAs such as leucine, interact functionally with intracellular nutrient-signaling pathways that regulate metabolism: for example, the mammalian target of rapamycin complex 1 (mTORC1) pathway, which promotes cell growth, and the general control non-derepressible (GCN) pathway, which is activated by AA starvation. Under some circumstances, upregulation of AA transporter expression [notably a leucine transporter, solute carrier 7A5 (SLC7A5)] is required to initiate AA-dependent activation of the mTORC1 pathway. Certain AA transporters may have dual receptor-transporter functions, operating as "transceptors" to sense extracellular (or intracellular) AA availability upstream of intracellular signaling pathways. New opportunities for nutritional therapy may include targeting of AA transporters (or mechanisms that upregulate their expression) to promote protein-anabolic signals for retention or recovery of lean tissue mass.

FIGURE 1.

Transporters and transceptors. The AA transport process proceeds through a sequence of steps as follows: 1) binding of AAs to a specific exposed site on the transporter at the (cis) membrane surface; 2) a change in conformation of the transporter, which results in the AA-bound site becoming exposed to the opposite (trans) membrane surface through the central pore; and 3) release of AAs and reorientation of the transporter to the initial cis-facing conformation. AA transport may be coupled to movements of ions including Na⁺, H⁺, K⁺, or Cl⁻ (see Figure 2). Certain AA transporters may also act as transceptors (ie, binding or translocation of AAs is coupled to activation of an intracellular signaling cascade), enabling them to “sense” the size of the cis pool of AAs (10, 19). The signal may be generated directly by the transceptor: for example, by covalent modification (eg, phosphorylation) or proteolytic cleavage of an intracellular-signaling precursor or indirectly through an intermediate signal–generating molecule (represented here as a transmembrane SP). The SP produces a signal (arrows) in response to a conformational change in the transceptor due to AA binding/translocation. AA, amino acid; SP, signaling peptide.

FIGURE 2.

AA pools and nutrient sensing. Homeostasis of ECF and ICF pools of AAs depends on the balance between AA fluxes through transport and metabolic pathways. AA transporters function by specific mechanisms, which include uniport (facilitative transport; denoted as “A”), symport (cotransport; denoted as “B”), and antiport (exchange; denoted as “C”). Net delivery of AAs to the ICF pool by AA transporters in an adult consuming a balanced diet (equivalent to dietary AA intake at steady state) is ∼60–100 g/d (3, 66). The 2 major AA-sensitive signaling proteins in mammalian cells are GCN2 and mTOR (as part of mTORC1), which respond to changes in ICF AA concentrations as shown and regulate protein turnover (and hence cell growth). AA transceptors at the cell surface may also sense size and composition of the ECF pool of AAs. AA transceptors on intracellular membranes (not shown) may perform equivalent roles in sensing ICF pools of AAs. AA, amino acid; ECF, extracellular fluid; GCN2, general control non-derepressible 2; ICF, intracellular fluid; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin complex 1; SP, signaling peptide (this may generate or transmit the transceptor signal; see Figure 1 legend for further description).

FIGURE 3.

Neutral AA transporters and activation of the mTORC1 signaling pathway. This diagram shows the relation between neutral AA transport, intracellular AA concentration, and the mTORC1 growth signaling pathway in nonepithelial mammalian cells (see text for further details). A sequential relation between primary, secondary, and tertiary active transport systems (denoted as “I,” “II,” and “III,” respectively) contributes substantially to transport of LNAAs across cell membranes. Energy input is provided through ATP hydrolysis by the Na⁺/K⁺ pump (primary active transport). Note the operation of symport (cotransport) and antiport (exchange) mechanisms for AAs in series downstream of the Na⁺/ K⁺ pump. In epithelial cells, broad-scope neutral AA transporters provide both SNAAs and LNAAs coupled to ion fluxes by secondary active transport, lessening the requirement for step III. AA (principally LNAA) concentration and/or flux within intracellular compartments promotes recruitment of mTORC1 to lysosomes where it is activated by interactions with Rag and Rheb GTPases. Such activation of mTORC1, downstream of nutrient (AA) and growth factor (insulin) signals, stimulates protein synthesis and ribosome biogenesis by effector mechanisms as indicated. Both cytosolic and lysosomal AA sensors have been reported (see sections in text entitled “Plasma membrane AA transporters and cytosolic AA sensing upstream of mTORC1” and “AA transporters and lysosomal AA sensing upstream of mTORC1”). Remarkably little is known about the transporter or transporters mediating neutral AA uptake into lysosomes, although SLC38A7 has recently emerged as a candidate for this role (48). Intracellular AA metabolism may also modulate growth factor signaling upstream of mTORC1 (62, 63). AA, amino acid; Akt/PKB, protein kinase B; AMPK, adenosine monophosphate activated protein kinase; ECF, extracellular fluid; ICF, intracellular fluid; IRS-1, insulin receptor substrate 1; LNAA, large neutral amino acid; mTORC1, mammalian target of rapamycin complex 1; PDK1, 3-phosphoinositide dependent protein kinase 1; PI3-K, phosphatidylinositide 3-kinase; Rag, Ras-related GTPase; Rheb, Ras homolog enriched in brain; SLC36A1, solute carrier 36A1; SNAA, small neutral amino acid; TSC1/2, tuberous sclerosis complex 1/2; V-ATPase, vacuolar H⁺-ATPase; 4E-BP1, eukaryotic initiation factor 4E binding protein 1.