Placental Transfer and Fetal Requirements of Amino Acids

SLC1

The SLC1 family contains the accumulative anionic amino acid transporters that form System X _AG and the neutral amino acid exchangers comprising the System ASC (alanine, serine, and cysteine). Through System X _AG proteins, the amino acids glutamate and aspartate are taken up into the placenta by the highly accumulative excitatory amino acid transporters (EAATs; SLC1A1-3, 6, and 7). The EAATs mediate sodium-coupled uptake of anionic amino acids and are found on both the MVM and BM of the placenta. ^, The rat BM preparation is reported to have a higher maximal velocity, an observation that is consistent with the predominant flux of glutamate from the fetus to the placenta, as has been demonstrated in the sheep and human. ^, EAAT-1, EAAT-2, and EAAT-3 have been detected in human placental tissue. The regulation of these proteins appears to be under the control of growth hormone (GH) and insulin-like growth factor (IGF) family members, both of which are regulated by nutrient supply, as shown in rodent cell line culture nutrient deprivation studies. ^,

ASCT1 (SLC1A4) and ASCT2 (SLC1A5) mediate sodium-dependent exchange of small neutral amino acids—alanine, serine, and cysteine—originally termed the ASC transport proteins. These transporters have been found in the MVM and in the BM. Hypoxia is reported to inhibit or limit their expression, and levels are reduced in placentae with growth-restricted fetuses. Both ASCT1 and ASCT2 are expressed in placental tissue ^, and play additional critical roles in cytotrophoblast fusion into the syncytiotrophoblast.

SLC6

The taurine transporter (TAUT) (SLC6A6) has been found in MVM placental tissue and is thought to be important in maintaining the high intracellular concentrations of taurine observed in the human placenta. Taurine is essential for fetal growth and is thought to be important in maintaining osmotic balance and functioning as an antioxidant. In addition to transporting taurine into the placenta, the TAUT transporter potentially mediates the bilateral release of taurine into maternal and fetal circulations. Studies examining the impact of obesity on placental function have reported that placental TAUT activity at term is negatively related to maternal body mass index (BMI).

SLC7

The SLC7 family contains a large number of amino acid transporters that are relevant to placental function, including the transporters that constitute System L, System y ⁺ , and System y ⁺ L. LAT1 (SLC7A5) and 2 (SLC7A8) are exchange transporters that mediate transfer of neutral amino acids and, characteristic of System L, mediate transfer of the L-system-specific substrate 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH). These transporters, especially LAT2, have a broad substrate specificity for the neutral amino acids. Functional System L activity occurs through specific light chain proteins associated with 4F2hc. System L activity is reported on both the MVM and BM. Immunologic and functional studies suggest that at term gestation, the light chain LAT1 is located predominantly in the MVM. ^, Furthermore, the L transport system phenotype associated with the MVM occurs when the LAT1 catalytic subunit is coexpressed with the 4F2hc, not LAT2. ^, Human LAT2 mRNA also has been reported in human choriocarcinoma BeWo cells and placental villous tissues. Placental BM studies concerning the inhibition of specific amino acid and/or synthetic amino acid uptake have determined that the BM L transport system phenotype is associated with the coexpression of LAT2 and 4F2hc, and not LAT2, as observed to occur in the MVM. ^{, ,} Furthermore, regulation of placental System L activity does not seem to be under the control of hypoxia, although evidence exists that it may not be the case in other cell preparations. ^, Although evidence is lacking in placental preparations, IGF-1 appears to regulate System L activity where chronic infusions of IGF-1 have corrected impaired transport of leucine in the brush border of the rat intestine. Additionally, in a mouse model of intrauterine growth restriction (IUGR), System L remained at control levels after Ad-hIGF-1 administration.

The transport of cationic amino acids occurs through the CAT and the y ⁺ LAT transporters. The cationic amino acid transporter (CAT) activity is associated with System y ⁺ activity and in placental cell culture and human placental studies, CAT 1 (SLC7A1), 2B (SLC7A2), and 3 (SLC7A3) are expressed. ^, In contrast to the other SCL7 family transporters the CATs do not require a heavy chain for their activity. ^, CAT activity has been extensively studied in the rodent and human placenta. In human preparations, CAT activity has been localized to the MVM and BM, although conflicting data exist as to y ⁺ activity in the BM. ^,

System y ⁺ L activity is mediated by the transporters y ⁺ LAT1 (SLC7A7) and y ⁺ LAT2 (SLC7A6). ^{, ,} y ⁺ LATs are exchangers for cationic amino acids and sodium dependent exchangers for neutral amino acids. The effect of this selective Na-dependence is that they preferentially mediate efflux of cationic amino acids (as intracellular sodium concentrations are low, precluding efflux of neutral amino acids). y ⁺ LAT activity is localized to both the MVM and BM. ^{, ,} This system may play an essential role in supplying cationic amino acids to the fetus by exchanging cationic amino acids within the trophoblast for neutral amino acids from the fetal circulation. ^{, ,}