Amino acid transporters and nutrient-sensing mechanisms: new targets for treating insulin-linked disorders?

Abstract

The IIS (insulin/IGF (insulin-like growth factor) signalling) cascade has an important role in regulating normal development and physiology, as evidenced by its effects in a host of major human diseases including cancer, Type 2 diabetes and neurodegeneration. Recently, it has become clear that multiple types of local nutrient-sensing mechanisms have an impact on cellular insulin-sensitivity through the downstream kinase TOR (target of rapamycin). In vivo analysis in flies has surprisingly highlighted PATs (proton-assisted amino acid transporters) as having a uniquely potent role in regulating IIS/TOR activity and growth, potentially via a novel signalling mechanism. Other molecules such as the heterodimeric amino acid transporter, CD98, which provides the principal route for cellular uptake of leucine, an amino acid implicated in regulating TOR, also appear to have important effects. As our understanding of how nutrient sensing has an impact on IIS/TOR increases, novel targets to modulate aberrant IIS in disease are likely to emerge, which could complement current strategies designed to block kinases in this pathway.

An increase in essential amino acid availability upregulates amino acid transporter expression in human skeletal muscle

“…Much attention has been given to the L-and A-type amino acid transporters as central for delivering substrates to nutrient sensors upstream of mTORC1. However, a scan of the literature shows that PAT transporters are important for cell growth in Drosophila and also operate through an mTORC1-related mechanism (16,40). Godberdhan and colleagues (17) proposed a model in which PAT transporters not only transport amino acids directly into the cytosol but may also act as a shuttle to transport amino acids, such as leucine, directly to mTORC1.…”

“…Furthermore, we determined the expression pattern of the PAT transporters, newly reported transporters with a role in muscle growth and associated mTOR signaling (16,40), following EAA ingestion. PAT1 mRNA expression was increased at 1 h following EAA ingestion ( Fig.…”

“…Therefore, the primary aim of this experiment was to determine the expression levels of L-type (LAT1/SLC7A5, y ϩ LAT1/SLC7A7, LAT3/SLC43A1, and CD98/SLC3A2) and A-type (SNAT2/SLC38A2 and SNAT4/SLC38A4) amino acid transporters in relation to leucine kinetics in human skeletal muscle following the ingestion of EAA. A secondary aim was to determine the effect of an increase in EAA availability on the response of additional amino acid transporters associated with muscle growth and mTOR signaling [proton-coupled amino acid transporter (PAT1/SLC36A1 and PAT2/SLC36A2)] (16,40), transporters that have not been linked to the mTORC1 signaling pathway [cationic amino acid transporter (CAT2/SLC7A2) and excitatory amino acid transporter (EAAT1/SLC1A3)], and members of the general amino acid control pathway [GCN2, eIF2␣ (Ser 52 ), and ATF4]. We hypothesized that an increase in EAA availability would stimulate ATF4 and amino acid transporter expression.…”

CD98 at the crossroads of adaptive immunity and cancer

“…The light chain functions in amino acid transport (Deves and Boyd, 2000;Verrey, 2003); some of the light chains have broad specificity, but the large neutral amino acid transporters LAT-1 and LAT-2 (encoded by SLC7A6 and SLC7A8), which are the best-studied, have preference for importing certain essential amino acids, particularly leucine, isoleucine and arginine (LAT-1), in exchange for glutamine (Bertran et al, 1992;Palacin, 1994;Pineda et al, 1999;Torrents et al, 1998;Verrey, 2003;Verrey et al, 2000). Indeed, through this nutrient function, CD98 can contribute to the survival and growth of many cell types (Cho et al, 2004;Reynolds et al, 2007). Importantly, surface expression of the light chain is dependent on the presence of the heavy chain, whereas the isolated heavy chain can be expressed without light chains (Cantor et al, 2009;Cantor et al, 2011;Mastroberardino et al, 1998;Teixeira et al, 1987).…”

SLC36A4 (hPAT4) Is a High Affinity Amino Acid Transporter When Expressed in Xenopus laevis Oocytes

“…As for PATH, it seems likely that under many physiological conditions, hPAT4 will always be saturated, and due to its low capacity, its role as a bulk transporter is open to question. Whether hPAT4 is a transceptor is an interesting and important area of future research due to the implication of the mammalian TOR/S6-kinase signaling pathway in diseases such as cancer and diabetes (32).…”