Loss of function mutation of the Slc38a3 glutamine transporter reveals its critical role for amino acid metabolism in the liver, brain, and kidney.
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.
Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.|Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
Kessara
K
Chan
Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland.
Stephanie M
SM
Busque
ZIEL Research Center of Nutrition and Food Sciences, Department of Biochemistry, Technische Universität München, Freising, Germany.
Manuela
M
Sailer
Ingenium, Munich, Germany.
Claudia
C
Stoeger
Research School of Biology, Australian National University, Canberra, Australia.
Stefan
S
Bröer
ZIEL Research Center of Nutrition and Food Sciences, Department of Biochemistry, Technische Universität München, Freising, Germany.
Hannelore
H
Daniel
Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland. isabel.rubioaliaga@uzh.ch.|ZIEL Research Center of Nutrition and Food Sciences, Department of Biochemistry, Technische Universität München, Freising, Germany. isabel.rubioaliaga@uzh.ch.
Isabel
I
Rubio-Aliaga
Institute of Physiology and Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland. wagnerca@access.uzh.ch.
Carsten A
CA
Wagner
D000595:Amino Acid Sequence; D026921:Amino Acid Transport Systems, Neutral / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D026921:Amino Acid Transport Systems, Neutral; D000596:Amino Acids; C403222:system N protein 1; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
Amino acid transport; Ammoniagenesis; Glutamine metabolism; Mouse model; mTOR pathway