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Biochem Biophys Res Commun
2018 Nov 17;5061:237-242. doi: 10.1016/j.bbrc.2018.10.074.
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Estrone sulphate uptake by the microvillous membrane of placental syncytiotrophoblast is coupled to glutamate efflux.
Lofthouse EM
,
Cleal JK
,
O'Kelly IM
,
Sengers BG
,
Lewis RM
.
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Organic anion transporters (OATs) and organic anion transporting polypeptides (OATPs) are transport proteins that mediate exchange of metabolites, hormones and waste products. Directional transport by these transporters can occur when exchange is coupled to the gradients of other substrates. This study investigates whether the activity of OATP4A1 and OATP2A1 on the maternal facing microvillus membrane of the placental syncytiotrophoblast is coupled to the glutamate gradient. OAT and OATP transporter proteins were over expressed in Xenopus oocytes to study their transport characteristics. Further transport studies were performed in term human placental villous fragments. Xenopus oocytes expressing OATP4A1 mediated glutamate uptake. No glutamate transport was observed in oocytes expressing OAT1, OAT3, OAT7 or OATP2A1. In oocytes expressing OATP4A1, uptake of estrone sulphate, thyroid hormones T3 and T4 and the bile acid taurocholate stimulated glutamate efflux. In term placental villous fragments addition of estrone sulphate and taurocholate trans-stimulated glutamate efflux. Coupling of OATP4A1 to the glutamate gradient may drive placental uptake of estrone-sulphate and thyroid hormone while also facilitating uptake of potentially harmful bile acids. In contrast, if OATP2A1 is not coupled to a similar gradient, it may function more effectively as an efflux transporter, potentially mediating efflux of prostaglandins to the mother. This study provides further evidence for glutamate as an important counter-ion driving transport into the placenta.
Fig. 1. OATP4A1 mediates glutamate uptake A) OATP2B1 and OATP4A1 are inhibited by glutamate. 3H-ES uptake in transporter expressing oocytes was inhibited by 2.5 mM ES (*p < 0.05, n = 3 experiments, 10 oocytes per condition). 2.5 mM glutamate (Glu) inhibited 3H-ES uptake in OATP2B1 and OATP4A1 expressing oocytes (ϕ p < 0.001). Data are adjusted for water injected oocyte responses. B) OATP4A1 mediated 14C-glutamate uptake is inhibited by OATP4A1 substrates. Under sodium free conditions, 14C-glutamate uptake is inhibited by 2.5 mM glutamate estrone sulphate, BSP and alpha ketoglutarate (*p < 0.05, n = 3 ovaries). Data are adjusted for water injected background responses and presented as mean (SEM).
Fig. 2. Glutamate efflux is coupled to uptake of thyroid hormone and taurocholate in OATP4A1 expressing Xenopus oocytes. A) 14C-glutamate efflux was stimulated by 2.5 mM estrone sulphate, (*p = 0.03) and 2.5 mM glutamate (**p < 0.01) in OATP4A1 expressing oocytes but not by OAT1, OAT3, OAT5, OAT7 or OATP2A1 (n = 3 individual ovaries, 10 oocytes per condition). B) 14C-glutamate efflux time course from 0 to 10 min in OATP4A1 expressing oocytes. 14C-glutamate efflux is significantly higher compared to water injected control oocytes (p = 0.05, n = 3 individual ovaries, 5 × 3 oocytes per condition). C) 14C-gluatamte efflux was stimulated by 2.5 mM glutamate (*p = 0.03) and 2.5 mM estrone sulphate (*p = 0.01) although stimulation by 2.5 mM BSP did not reach statistical significance (#p = 0.08) under sodium free conditions (n = 5 individual ovaries, 5 × 3 oocytes per condition). D) 14C-gluatamte efflux is stimulated by OATP4A1 substrates 100 μM thyroxine (T4, **p < 0.001), 100 μM triiodothyronine (T3, *p = 0.014) and 2.5 mM taurocholate (**p < 0.001) but not by glycine (n = 5 individual ovaries, 5 × 3 oocytes per condition). Data are adjusted for background water injected responses and presented as mean and SEM.
Fig. 3. Uptake of OATP4A1 substrates is coupled glutamate efflux in placental villous fragments. 1 mM OATP4A1 substrates; estrone sulphate, glutamate and taurocholate but not by glycine (p < 0.05, n = 5 experiments, 3 fragments per condition, 3 replicates). Data are presented as mean and SEM.
Fig. 4. Intra-oocyte glutamate injection trans-stimulates estrone sulphate uptake in oocytes expressing OATP2A1 despite the fact that glutamate does not appear to be an OATP2A1 substrate. Compared to 3H-ES uptake alone in OATP2A1 oocytes, uptake was inhibited by cold ES, but not by glutamate. The injection of 5 mM glutamate into OATP2A1 expressing oocytes resulted in a trans-stimulation of 3H-ES uptake (p = 0.006). Data are analysed by two-way ANOVA and presented as mean and SEM and adjusted for water injected responses (n = 3 individual ovaries, 5 oocytes per condition).
Fig. 5. OATs/OATPs in the syncytiotrophoblast and their interaction with substrates and other transport systems. Uptake of thyroid hormone by OATP4A1 would allow its transport to the fetus by TAT1 (SLC16A10). If OATP2A1 is not coupled to an outwardly directed gradient it would be able to act as an efflux transporter. Uptake of DHEAS by OATP2A1 will facilitate placental oestrogen synthesis.
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