CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch

Institute of Physiology, University of Zürich, Winterthurerstrasse 190, 8057, Zürich, Switzerland,
Pflügers Archiv - European Journal of Physiology (Impact Factor: 4.1). 03/2004; 447(5):532-42. DOI: 10.1007/s00424-003-1086-z
Source: PubMed


The SLC7 family is divided into two subgroups, the cationic amino acid transporters (the CAT family, SLC7A1-4) and the glycoprotein-associated amino acid transporters (the gpaAT family, SLC7A5-11), also called light chains or catalytic chains of the hetero(di)meric amino acid transporters (HAT). The associated glycoproteins (heavy chains) 4F2hc (CD98) or rBAT (D2, NBAT) form the SLC3 family. Members of the CAT family transport essentially cationic amino acids by facilitated diffusion with differential trans-stimulation by intracellular substrates. In some cells, they may regulate the rate of NO synthesis by controlling the uptake of l-arginine as the substrate for nitric oxide synthase (NOS). The heterodimeric amino acid transporters are, in contrast, quite diverse in terms of substrate selectivity and function (mostly) as obligatory exchangers. Their selectivity ranges from large neutral amino acids (system L) to small neutral amino acids (ala, ser, cys-preferring, system asc), negatively charged amino acid (system x(c)(-)) and cationic amino acids plus neutral amino acids (system y(+)L and b(0,+)-like). Cotransport of Na(+) is observed only for the y(+)L transporters when they carry neutral amino acids. Mutations in b(0,+)-like and y(+)L transporters lead to the hereditary diseases cystinuria and lysinuric protein intolerance (LPI), respectively.

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    • "system)], which was dysregulated in ALS, HD, MS, PD, and schizophrenia. SLC7A9 is a glycoprotein-associated amino acid transporter showing high-affinity for L-cystine (Verrey et al. 2004), which is essential in the synthesis of antioxidant glutathione released in response to oxidative stress (Aoyama et al. 2008). In addition, the heat shock protein DNAJB6 (DnaJ (Hsp40) homolog, subfamily B, member 6) was upregulated in HD, MS, and PD. "
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    ABSTRACT: Neurodegenerative diseases of the central nervous system are characterized by pathogenetic cellular and molecular changes in specific areas of the brain that lead to the dysfunction and/or loss of explicit neuronal populations. Despite exhibiting different clinical profiles and selective neuronal loss, common features such as abnormal protein deposition, dysfunctional cellular transport, mitochondrial deficits, glutamate excitotoxicity, iron accumulation and inflammation are observed in many neurodegenerative disorders, suggesting converging pathways of neurodegeneration. We have generated comparative genome-wide gene expression data, using the Illumina HumanRef 8 Beadchip, for Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, Parkinson's disease, and schizophrenia using an extensive cohort (n = 113) of well-characterized post-mortem brain tissues. The analysis of whole-genome expression patterns across these major disorders offers an outstanding opportunity not only to look into exclusive disease-specific changes, but more importantly to look for potential common molecular pathogenic mechanisms. Surprisingly, no dysregulated gene that passed our selection criteria was found in common across all six diseases. However, 61 dysregulated genes were shared when comparing five and four diseases. The few genes highlighted by our direct gene comparison analysis hint toward common neuronal homeostatic, survival and synaptic plasticity pathways. In addition, we report changes to several inflammation-related genes in all diseases. This work is supportive of a general role of the innate immune system in the pathogenesis and/or response to neurodegeneration.
    Journal of Neural Transmission 08/2014; 122(7). DOI:10.1007/s00702-014-1293-0 · 2.40 Impact Factor
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    • "Muscle-specific knockout of the Slc7a5 gene (MS-Slc7a5-KO) in mice results in substantial reductions of both Slc7a5 mRNA expression and LNAA transport function in the skeletal muscles studied. Skeletal muscle expresses both high-affinity and low-affinity System L1 transporters for LNAA (SLC7A5 and SLC7A8 respectively), in common with several other tissues [7]. The low phenylalanine concentration (5 µM) used for our in vitro transport studies disproportionately favours uptake by the high-affinity SLC7A5 transporter over other LNAA transporters expressed in muscle, so the reduction of muscle LNAA uptake in vivo due to Slc7a5 knockout is likely to be less than the ∼75% reductions shown in Figures 2B, 3B and S1A. "
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    ABSTRACT: The System L1-type amino acid transporter mediates transport of large neutral amino acids (LNAA) in many mammalian cell-types. LNAA such as leucine are required for full activation of the mTOR-S6K signalling pathway promoting protein synthesis and cell growth. The SLC7A5 (LAT1) catalytic subunit of high-affinity System L1 functions as a glycoprotein-associated heterodimer with the multifunctional protein SLC3A2 (CD98). We generated a floxed Slc7a5 mouse strain which, when crossed with mice expressing Cre driven by a global promoter, produced Slc7a5 heterozygous knockout (Slc7a5+/-) animals with no overt phenotype, although homozygous global knockout of Slc7a5 was embryonically lethal. Muscle-specific (MCK Cre-mediated) Slc7a5 knockout (MS-Slc7a5-KO) mice were used to study the role of intracellular LNAA delivery by the SLC7A5 transporter for mTOR-S6K pathway activation in skeletal muscle. Activation of muscle mTOR-S6K (Thr389 phosphorylation) in vivo by intraperitoneal leucine injection was blunted in homozygous MS-Slc7a5-KO mice relative to wild-type animals. Dietary intake and growth rate were similar for MS-Slc7a5-KO mice and wild-type littermates fed for 10 weeks (to age 120 days) with diets containing 10%, 20% or 30% of protein. In MS-Slc7a5-KO mice, Leu and Ile concentrations in gastrocnemius muscle were reduced by ∼40% as dietary protein content was reduced from 30 to 10%. These changes were associated with >50% decrease in S6K Thr389 phosphorylation in muscles from MS-Slc7a5-KO mice, indicating reduced mTOR-S6K pathway activation, despite no significant differences in lean tissue mass between groups on the same diet. MS-Slc7a5-KO mice on 30% protein diet exhibited mild insulin resistance (e.g. reduced glucose clearance, larger gonadal adipose depots) relative to control animals. Thus, SLC7A5 modulates LNAA-dependent muscle mTOR-S6K signalling in mice, although it appears non-essential (or is sufficiently compensated by e.g. SLC7A8 (LAT2)) for maintenance of normal muscle mass.
    PLoS ONE 02/2014; 9(2):e89547. DOI:10.1371/journal.pone.0089547 · 3.23 Impact Factor
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    • "Among many amino acid transporters, system xc− is a heterodimeric transporter comprised of a light chain, xCT (xc− transporter) and heavy chain (4F2hc) which mediates the exchange of extracelluar cystine and intracellular glutamate at the plasma membrane [4, 32]. As a heterodimeric transporter, system xc− requires both xCT and 4F2hc for its activity as a functional transport-unit of this carrier protein, which belongs to the SLC7 gene family [35]. "
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    ABSTRACT: ABSTRACTThe cystine transport activity of a lens epithelial cell line originated from a canine mature cataract was investigated. The distinct cystine transport activity was observed, which was inhibited to 28% by extracellular 1 mM glutamate. The cDNA sequences of canine cysteine/glutamate exchanger (xCT) and 4F2hc were determined. The predicted amino acid sequences were 527 and 533 amino acid polypeptides, respectively. The amino acid sequences of canine xCT and 4F2hc showed high similarities (>80%) to those of humans. The expression of xCT in lens epithelial cell line was confirmed by western blot analysis. RT-PCR analysis revealed high level expression only in the brain, and it was below the detectable level in other tissues.
    Journal of Veterinary Medical Science 12/2013; 76(4). DOI:10.1292/jvms.13-0170 · 0.78 Impact Factor
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