The SNAT4 isoform of the system A amino acid transporter is functional in human placental microvillous plasma membrane

Abstract

Placental system A activity is important for the supply of neutral amino acids needed for fetal growth. There are three system A isoforms: SNAT1, SNAT2 and SNAT4, but the contribution of each to system A-mediated transport is unknown. Here, we have used immunohistochemistry to demonstrate that all three isoforms are present in the syncytiotrophoblast suggesting each plays a role in amino acid transport across the placenta. We next tested the hypothesis that the SNAT4 isoform is functional in microvillous plasma membrane vesicles (MVM) from normal human placenta using a method which exploits the unique property of SNAT4 to transport both cationic amino acids as well as the system A-specific substrate MeAIB. The data show that SNAT4 contribution to system A-specific amino acid transport across MVM is higher in first trimester placenta compared to term (approx. 70% and 33%, respectively, P < 0.01). Further experiments performed under more physiological conditions using intact placental villous fragments suggest a contribution of SNAT4 to system A activity in first trimester placenta but minimal contribution at term. In agreement, Western blotting revealed that SNAT4 protein expression is higher in first trimester MVM compared to term (P < 0.05). This study provides the first evidence of SNAT4 activity in human placenta and demonstrates the contribution of SNAT4 to system A-mediated transport decreases between first trimester and term: our data lead us to speculate that at later stages of gestation SNAT1 and/or SNAT2 are more important for the supply of amino acids required for normal fetal growth.

SNAT2 expression and regulation in human growth-restricted placentas

“…Immunohistochemical data confirmed that in human placentas, SNAT2 is expressed in the villous trophoblast, in both the syncytio-and cytotrophoblast (26). However, in IUGR placentas, SNAT2 staining intensity seemed to be lower in the syncytiotrophoblast.…”

“…Finally, because the other SNAT gene isoforms (SNAT1 and SNAT4) may contribute to System A amino acid transporter activity in the human placental trophoblast (26), the analysis of their expression in this study population might clarify the role of System A amino acid transporter deregulation in the etiopathogenesis of intrauterine growth restriction.…”

Expression and Role of SNAT3 in the Placenta

“…System A and system y + L are expressed at high levels in the placenta in the late stage of gestation. These results tend to be consistent with the previous studies [26,34,35]. Moreover, it has been reported that system A plays a key role in glutamine transport from the maternal side into placental cells [18,33].…”

“…However, little is known about the expression of nutrient transporters in the early period of gestation or their expression in cytotrophoblast cells [26]. …”

The Role of the Placenta in Fetal Programming

“…It is located in the syncytiotrophoblast and consists of three isoforms: SNAT1, SNAT2, SNAT4. The expression of these different isoforms changes in the human placenta during pregnancy (Desforges et al 2009). In vitro studies with human placental explants or trophoblast cells showed that SNAT proteins are upregulated by insulin, leptin and IGF-I and down-regulated by hypoxemia, nitric oxide and free oxygen radicals (Jones et al 2007).…”