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Multifaceted Chaudhry.Pdf Neuropharmacology 161 (2019) 107789 Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm Invited review Multifaceted regulation of the system A transporter Slc38a2 suggests T nanoscale regulation of amino acid metabolism and cellular signaling ∗ Robin Johansen Menchinia, , Farrukh Abbas Chaudhrya,b a Department of Molecular Medicine, University of Oslo, Oslo, Norway b Department of Plastic and Reconstructive Surgery, Oslo University Hospital, Oslo, Norway HIGHLIGHTS • Slc38a2 represents the classically described system A transport activity. • Slc38a2 accumulates small, neutral amino acids directly or indirectly by energizing ASCT1/2 and LAT1/2 transporters. • Slc38a2 is extensively regulated by cell stress, nutritional and hormonal signaling, and acts as an amino acid sensor upstream of mTOR. • Slc38a2 contributes to the pathology in a number of diseases such as cancer, epilepsy and diabetes mellitus. ARTICLE INFO ABSTRACT Keywords: Amino acids are essential for cellular protein synthesis, growth, metabolism, signaling and in stress responses. Slc38a1 Cell plasma membranes harbor specialized transporters accumulating amino acids to support a variety of cellular Slc38a2 biochemical pathways. Several transporters for neutral amino acids have been characterized. However, Slc38a2 SNAT2 (also known as SA1, SAT2, ATA2, SNAT2) representing the classical transport system A activity stands in a Glutamine unique position: Being a secondarily active transporter energized by the electrochemical gradient of Na+, it Osmoregulation creates steep concentration gradients for amino acids such as glutamine: this may subsequently drive the ac- Adaptive regulation cumulation of additional neutral amino acids through exchange via transport systems ASC and L. Slc38a2 is ubiquitously expressed, yet in a cell-specific manner. In this review, we show that Slc38a2 is regulated atthe transcriptional and translational levels as well as by ions and proteins through direct interactions. We describe how Slc38a2 senses amino acid availability and passes this onto intracellular signaling pathways and how it regulates protein synthesis, cellular proliferation and apoptosis through the mechanistic (mammalian) target of rapamycin (mTOR) and general control nonderepressible 2 (GCN2) pathways. Furthermore, we review how this extensively regulated transporter contributes to cellular osmoadaptation and how it is regulated by endoplasmic reticulum stress and various hormonal stimuli to promote cellular metabolism, cellular signaling and cell sur- vival. This article is part of the issue entitled ‘Special Issue on Neurotransmitter Transporters’. 1. Introduction metabolism and apoptosis (Wu, 2009). Glutamine is the most abundant amino acid in both plasma and cere- 1.1. Physiological roles of amino acids brospinal fluid (Curi et al., 2005). It plays a pivotal role in intermediary metabolism, as a nitrogen and carbon donor, in pH homeostasis and as a Amino acids play a number of roles in human metabolism. In addition substrate for biosynthetic pathways for neurotransmitters, glutathione, to their appearance as substrates for protein synthesis, amino acids act as proteins, nucleotides and amino sugars (Chaudhry et al., 2002a). Glutamine sources of energy, carbon, nitrogen, metabolic intermediaries as well as is the preferred nutrient for rapidly dividing cells such as immune cells, precursors for the synthesis of macromolecules such as hormones, he- enterocytes and cancer cells (Cruzat et al., 2018). Glutamine is a non-es- moglobin and cytochromes. In later years, it is recognized that amino acids sential amino acid, but it may become conditionally essential during cata- such as glutamine, leucine and arginine double as regulators of cell growth, bolic states as cellular demands increase. ∗ Corresponding author. E-mail address: [email protected] (R.J. Menchini). https://doi.org/10.1016/j.neuropharm.2019.107789 Received 19 April 2019; Received in revised form 16 September 2019; Accepted 20 September 2019 Available online 28 September 2019 0028-3908/ © 2019 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). R.J. Menchini and F.A. Chaudhry Neuropharmacology 161 (2019) 107789 1.2. Uptake systems for the neutral amino acids optic nerve pathology (Poulter et al., 2013; Perez et al., 2014; Toral et al., 2017). Slc38a7 is a lysosomal transporter suggested to be the In critically ill patients admitted to intensive care units, both low main carrier of glutamine across lysosomal membranes and required for and high plasma levels of glutamine are associated with a poor clinical cancer cell growth in periods of low glutamine availability (Verdon outcome (Oudemans-van Straaten et al., 2001; Rodas et al., 2012). et al., 2017). Slc38a9, like Slc38a7, is located on lysosomal membranes. Supplementing critically ill patients with parenteral glutamine sig- Recently, three independent laboratories showed that Slc38a9 is part of nificantly reduced hospital mortality, length of stay and rate ofin- the Rag GTPase-Ragulator amino acid-sensing machinery that controls fectious complications and more (Stehle et al., 2017). Thus, main- the activity of mechanistic target of rapamycin complex 1 (mTORC1) taining optimal concentrations of the amino acid plasma pool is (Rebsamen et al., 2015; Wang et al., 2015; Jung et al., 2015). In part, essential for homeostasis in healthy individuals. Several active and this is achieved through Slc38a9-mediated release of leucine, as concentrative transport systems for neutral amino acids across cell Slc38a9 is needed to transport several essential amino acids generated membranes have been demonstrated (Palacin et al., 1998). Glutamine is by proteolysis out of lysosomes (Wyant et al., 2017). Additionally, transported by the system A (alanine preferring) and system N (amide Slc38a9 transport activity may play a pivotal role in mTORC1 activa- preferring) activities originally described as Na+-dependent glutamine tion under conditions in which cells obtain amino acids by degrading transport activities in Ehrlich cells and hepatocytes, respectively extracellular proteins through macropinocytosis (Wyant et al., 2017). (Oxender and Christensen, 1963; Christensen et al., 1965; Kilberg et al., Within the Slc38 family, Slc38a9-a11 are the phylogenetically oldest 1980). Together with systems ASC (alanine, serine and cysteine pre- members with orthologues in C. elegans and D. melanogaster, while ferring) and L (leucine preferring), system A accounts for the majority Slc38a1-a5 have arisen later in evolutionary terms (Schioth et al., of amino acid uptake in mammalian cells (Palacin et al., 1998). Unlike 2013). As more Slc38 family amino acid transporters have been char- systems ASC and L, which are obligatory exchangers, system A cata- acterized, the dependence on Na+ and the division into systems A and lyzes the net uptake of a wider range of neutral amino acids, particu- N have become less distinct and additional spectacular mechanisms add larly alanine, serine, proline and glutamine. It is competitively inhibited to their function and regulation. by the non-metabolizable system A substrate analogue N-methyl-ami- noisobutyric acid (MeAIB) (Oxender and Christensen, 1963; 2. Slc38a2 characteristics Christensen et al., 1965). System N is characterized by transporting glutamine, histidine and asparagine, and tolerates Li+ substitution for 2.1. Slc38a2 structure Na+ (Kilberg et al., 1980). However, the molecular identity of the proteins responsible escaped discovery for decades (Barker and Ellory, The Slc38a2 gene consists of 16 exons and 15 introns in humans and 1990; Palacin et al., 1998). rodents (Palii et al., 2004). Exon 1 encodes most of the 5′-untranslated region (5′-UTR), while the start and stop codons are located in exon 2 1.3. Identification of the solute carrier 38 (Slc38) family of aminoacid and 16, respectively (Palii et al., 2004). Upon molecular characteriza- transporters tion, Slc38a2 was predicted to have (Reimer et al., 2000; Yao et al., 2000), and was recently demonstrated to have eleven transmembrane The field of system A and system N transporters was notopened domains, an intracellular N-terminus and an extracellular C-terminus until the group of Robert Edwards cloned the vesicular GABA trans- (Ge et al., 2018)(Fig. 1). Slc38a2 contains three N-glycosylation sites, porter (VGAT, also known as (aka) vesicular inhibitory amino acid Asn254, Asn258 and Asn272, which seem to play a part in protein ex- transporter (VIAAT)) (McIntire et al., 1997). Later, Chaudhry in colla- pression (Ge et al., 2018). The Slc38a2 protein also contains a disulfide boration with Edwards successfully identified and characterized the bridge between cysteine residues 245 and 279 situated in the third first system N transporter SN1 from its sequence homology toVGAT extracellular loop between transmembrane domains 5 and 6 (Chen (Chaudhry et al., 1999). Further molecular characterization revealed et al., 2016). Cys245 and Cys279 are highly conserved, and had reg- SN1 as the first identified member of the solute carrier (Slc) family 38of ulatory impact on Slc38a2 transport activity without them being re- amino acid transporters (Chaudhry et al., 2002a; Nissen-Meyer and quired for transport activity or trafficking to the plasma membrane Chaudhry, 2013; Broer, 2014). Together, the Slc32, Slc36 and Slc38 (Chen et al., 2016)(Fig.
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