The sodium-dependent glutamine transporter, Slc38a3/SNAT3 is predominantely expressed in kidney, liver, and brain. In order to better understand the role of SNAT3 in vivo we generated a ENU-mutated mouse model. The mutation named “SLC38a3-Q263X” results in a premature stop codon that leads to complete loss of SNAT3 protein in homozygous mice. Heterozygous “SLC38a3-Q263X” mice show intermediate protein levels.

SNAT3 mutant mice showed a stunted growth, ataxia and premature death around day 18-20 after birth. Moreover, SNAT3 deletion caused hypoglycemia, reduced urinary ammonium and urea excretion and elevated plasma urea in mutant mice compared to WT. Furthermore, SNAT3 KO mice showed altered plasma amino acids concentrations (Alanine, tryptophane, tyrosine, histidine, leucine). In the brain, SNAT3 KO mouse showed a decrease in the expression of the SNAT5 glutamine transporter (mRNA) and a strong increase of the SNAT1 and LAT1 transporters. In the liver, mutant mice showed dysregulation of various enzymes of the urea cycle and glutamine synthesis but also related glutamine transporters. In the kidney, expression of enzymes involved in ammoniagenesis and amino acid transport were also diminished compared to WT littermates. An acid challenge in heterozygous mice demonstrated the ability of the mice to regulate acid-base homeostasis and to maintain ammoniagenesis by inducing the expression of ammoniagenic enzymes.

Thus, SNAT3 plays a major role in glutamine transport in brain, kidney and liver and affects important functions such as glutamate release in brain, ammoniagenesis in kidney, and urea cycle in liver.

Figure 1