The sodium-dependent neutral amino acid transporter, Slc38a3/SNAT3 is involved in the transport of glutamine in kidney, liver, and brain. In order to better understand the role of SNAT3 in vivo and to characterize SNAT3 in various murine tissues, we generated a ENU-mutated mouse model of SNAT3 expressing the mutation "SLC38a3-Q263X" coding for a single nucleotide polymorphism in this gene, thereby causing a premature stop codon. SNAT 3 mutant mice showed a stunted growth, ataxia and premature death around day 18–20 after birth. SNAT3 mRNA expression was significantly reduced in SNAT3 KO mouse compared to WT mouse in kidney, liver and brain. SNAT3 protein was undetectable in these organs confirming the knock out of the protein. SNAT3 deletion caused reduced urinary ammonium and urea excretion and elevated serum urea in mutant mice compared to WT. Studies of the heterozygous mice showed that SNAT3, PDG and PEPCK mRNA expression were significantly enhanced in kidneys from heterozygote mice after acid-loading in comparison to WT suggesting a compensation of the partial defect in SNAT3 protein by upregulation of their expression. In the brain, SNAT3 KO mouse showed a significant decrease of the expression of related SNAT5 glutamine transporter and the SLC1A2 glutamate transporter. In liver, mutant mice showed dysregulation of various enzymes of the urea cycle and glutamine synthesis. Our data suggest that SNAT3 plays a significant role in the regulation of glutamine fluxes in kidney, liver, and brain.

Figure 1