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The System L transporter facilitates cellular import of large neutral amino acids (AAs) such as Leu, a potent activator of the intracellular target of rapamycin (TOR) pathway, which signals for cell growth. System L is an AA exchanger, proposed to accumulate certain AAs by coupling to dissipation of concentration gradient(s) of exchange substrates generated by secondary active AA transporters such as System A (SNAT2). We addressed the hypothesis that this type of coupling (termed tertiary active transport) acts as an indirect mechanism to extend the range of AA stimulating TOR to those transported by both Systems A and L (e.g., Gln) through downstream enhancement of Leu accumulation. System A overexpression enabled Xenopus oocytes to accumulate substrate AAs (notably Ser, Gln, Ala, Pro, Met; totaling 2.6 nmol/oocyte) from medium containing a physiological AA mixture at plasma concentrations. Net accumulation of System L (4F2hc x LAT1) substrates from this medium by System L-overexpressing oocytes was increased by 90% (from 0.7 to 1.35 nmol/oocyte; mainly Leu, Ile) when Systems A and L were coexpressed, coincident with a decline in accumulation of specific System A substrates (Gln, Set, Met), as expected if the latter were also System L substrates and functional coupling of the transport Systems occurred. AA flux coupling was confirmed as trans-stimulation of Leu influx in System L-expressing oocytes by Gin injection (0.5 nmol/oocyte). The observed changes in Leu accumulation are sufficient to activate the TOR pathway in oocytes, although intracellular AA metabolism limits the potential for AA accumulation by tertiary active transport in this system. nutrient transport; target of rapamycin pathway; glutamine; leucine; amino acid exchanger

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 Ssyl transceptor) that, at least for SNAT2, the transceptor discriminates between extracellular and intracellular amino acid stimuli when evoking a signal. SNAT2; mammalian target of rapamycin; GCN2; transporters; receptors

The interaction between the uptake of thyroid hormones and aromatic amino acids was analyzed in sinusoidal membrane vesicles isolated from the livers of rats with normal or altered thyroid status. Thyroid status did not alter the kinetic characteristics of tryptophan uptake and 3,5,3'-triidothyroxine binding in rat liver sinusoidal membrane vesicles. Furthermore, trytophan transport in rat liver sinusoidal membrane vesicles were mediated by N-ethylmaleimide (NEM)-sensitive and NEM-resistant components.

The glutamine and glutamate transporters in skeletal muscle and heart appear to play a role in control of the steady-state concentration of amino acids in the intracellular space and, in the case of skeletal muscle at least, in the rate of loss of glutamine to the plasma and to other organs and tissues. This article reviews what is currently known about transporter characteristics and mechanisms in skeletal muscle and heart, the alterations in transport activity in pathophysiological conditions and the implications for anabolic processes and cardiac function of altering the availability of glutamine. The possibilities that glutamine pool size is part of an osmotic signaling mechanism to regulate whole body protein metabolism is discussed and evidence is shown from work on cultured muscle cells. The possible uses of glutamine in maintaining cardiac function perioperatively and in promoting glycogen metabolism are discussed. J. Nutr. 126: 1142S-1149S, 1996. INDEXING KEY WORDS: glutamine, glutamate, transport

An analysis of glutamine transport and metabolism in cultural rat muscle cells that are deficient in glutamine levels revealed that glutamine deprivation enhanced the glutamine synthesized activity three times the normal levels while glutaminase activity retained its normal values. Absence of glutamine activity in myotubes of rats failed to influence the kinetics of amino acid transport systems A, ASC and L.

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The neonatal skeletal rat muscle glutamine transport was examined in preconfluent monolayered, mononucleated myoblasts and in fused multinucleated, differentiated myotubes. Stereospecific, saturable, sodium-dependent glutamine infusion was observed in myoblasts and myotubes. Glutamine utilization was unaffected by the amino acids leucine, arginine, glutamate and 2-aminobicyclo-(2,2,1) heptane-2-carboxylate (BCH). Glutamine inactivation occurred due to histidine, asparagine and serine, where the former two were on a competitive basis. The enhanced glutamine transport was due to the inhibition of the insulin 2-(methyl-amino) isobutyrate.

Sarcolemmal marker enzymes 5'-nucleotidase and K-stimulated phosphatase are enriched in the sarcolemnal vesicles, isolated from human skeletal muscle. The muscle was obtained from surgery and the enrichment was about 14 fold. An inside negative membrane potential was stimulated by the glutamine transport. The Li-for-Na substitution was not tolerated by the alamine transport, which is Na dependent. The differences and similarities between the known system transporter in rat skeletal muscles and the principal glutamine transporter in the human skeletal muscle are demonstrated by the results.