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Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney

Pflügers Archiv - European Journal of Physiology volume 468, pages 213–227 (2016)Cite this article

Abstract

Glutamine, the most abundant amino acid in mammals, is critical for cell and organ functions. Its metabolism depends on the ability of cells to take up or release glutamine by transporters located in the plasma membrane. Several solute carrier (SLC) families transport glutamine, but the SLC38 family has been thought to be mostly responsible for glutamine transport. We demonstrate that despite the large number of glutamine transporters, the loss of Snat3/Slc38a3 glutamine transporter has a major impact on the function of organs expressing it. Snat3 mutant mice were generated by N-ethyl-N-nitrosurea (ENU) mutagenesis and showed stunted growth, altered amino acid levels, hypoglycemia, and died around 20 days after birth. Hepatic concentrations of glutamine, glutamate, leucine, phenylalanine, and tryptophan were highly reduced paralleled by downregulation of the mTOR pathway possibly linking reduced amino acid availability to impaired growth and glucose homeostasis. Snat3-deficient mice had altered urea levels paralleled by dysregulation of the urea cycle, gluconeogenesis, and glutamine synthesis. Mice were ataxic with higher glutamine but reduced glutamate and gamma-aminobutyric acid (GABA) levels in brain consistent with a major role of Snat3 in the glutamine-glutamate cycle. Renal ammonium excretion was lower, and the expression of enzymes and amino acid transporters involved in ammoniagenesis were altered. Thus, SNAT3 is a glutamine transporter required for amino acid homeostasis and determines critical functions in various organs. Despite the large number of glutamine transporters, loss of Snat3 cannot be compensated, suggesting that this transporter is a major route of glutamine transport in the liver, brain, and kidney.

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Acknowledgments

We thank François Verrey (Institute of Physiology, University of Zurich, Switzerland) for providing us with anti-SNAT1 and anti-SNAT3 antibodies and Norman Curthoys (Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO, USA) for providing us with the anti-PDG antibody. This study was supported by grants from the 6th EU frame work project EUGINDAT and the Swiss National Science Foundation (31003A_155959/1) to C.A. Wagner.

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Author notes

  1. Kessara Chan

    Present address: Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland

Affiliations

  1. Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland

    Kessara Chan, Stephanie M. Busque, Isabel Rubio-Aliaga & Carsten A. Wagner

  2. ZIEL Research Center of Nutrition and Food Sciences, Department of Biochemistry, Technische Universität München, Freising, Germany

    Manuela Sailer, Hannelore Daniel & Isabel Rubio-Aliaga

  3. Ingenium, Munich, Germany

    Claudia Stoeger

  4. Research School of Biology, Australian National University, Canberra, Australia

    Stefan Bröer

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  1. Kessara Chan
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Correspondence to Isabel Rubio-Aliaga or Carsten A. Wagner.

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Chan, K., Busque, S.M., Sailer, M. et al. Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney. Pflugers Arch - Eur J Physiol 468, 213–227 (2016). https://doi.org/10.1007/s00424-015-1742-0

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Keywords

  • Amino acid transport
  • Glutamine metabolism
  • Mouse model
  • Ammoniagenesis
  • mTOR pathway