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Functional characterization of dopamine and norepinephrine transport across the apical and basal plasma membranes of the human placental syncytiotrophoblast

Horackova, Hana, Karahoda, Rona, Vachalova, Veronika, Turkova, Helena, Abad, Cilia, Staud, Frantisek·2022·Scientific Reports
DOI 10.1038/s41598-022-15790-7
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Abstract

The human placenta represents a unique non-neuronal site of monoamine transporter expression, with pathophysiological relevance during the prenatal period. Monoamines (serotonin, dopamine, norepinephrine) are crucial neuromodulators for proper placenta functions and fetal development, including cell proliferation, differentiation, and neuronal migration. Accumulating evidence suggests that even a transient disruption of monoamine balance during gestation may lead to permanent changes in the fetal brain structures and functions, projecting into adulthood. Nonetheless, little is known about the transfer of dopamine and norepinephrine across the placental syncytiotrophoblast. Employing the method of isolated membranes from the human term placenta, here we delineate the transport mechanisms involved in dopamine and norepinephrine passage across the apical microvillous (MVM) and basal membranes. We show that the placental uptake of dopamine and norepinephrine across the mother-facing MVM is mediated via the high-affinity and low-capacity serotonin (SERT/SLC6A4) and norepinephrine (NET/SLC6A2) transporters. In the fetus-facing basal membrane, however, the placental uptake of both monoamines is controlled by the organic cation transporter 3 (OCT3/SLC22A3). Our findings thus provide insights into physiological aspects of dopamine and norepinephrine transport across both the maternal and fetal sides of the placenta. As monoamine transporters represent targets for several neuroactive drugs such as antidepressants, our findings are pharmacologically relevant to ensure the safety of drug use during pregnancy.

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Research works printed but not linked: 53

  1. Rosenfeld, C. S. The placenta-brain-axis. J. Neurosci. Res. 99, 271–283. https://doi.org/10.1002/jnr.24603 (2021). · DOI · Paper page
  2. McCarthy, D., Lueras, P. & Bhide, P. G. Elevated dopamine levels during gestation produce region-specific decreases in neurogenesis and subtle deficits in neuronal numbers. Brain Res. 1182, 11–25. https://doi.org/10.1016/j.brainres.2007.08.088 (2007). · DOI
  3. Todd, R. D. Neural development is regulated by classical neurotransmitters: Dopamine D2 receptor stimulation enhances neurite outgrowth. Biol. Psychiatry 31, 794–807 (1992). · DOI
  4. Popolo, M., McCarthy, D. M. & Bhide, P. G. Influence of dopamine on precursor cell proliferation and differentiation in the embryonic mouse telencephalon. Dev. Neurosci. 26, 229–244. https://doi.org/10.1159/000082140 (2004). · DOI
  5. Padbury, J. F. 5—Functional maturation of the adrenal medulla and peripheral sympathetic nervous system. Baillieres Clin. Endocrinol. Metab. 3, 689–705. https://doi.org/10.1016/S0950-351X(89)80049-7 (1989). · DOI
  6. Thomas, S. A., Matsumoto, A. M. & Palmiter, R. D. Noradrenaline is essential for mouse fetal development. Nature 374, 643–646. https://doi.org/10.1038/374643a0 (1995). · DOI · Paper page
  7. Macaron, C., Famuyiwa, O. & Singh, S. P. In vitro effect of dopamine and pimozide on human chorionic somatomammotropin (hCS) secretion*. J. Clin. Endocrinol. Metab. 47, 168–170. https://doi.org/10.1210/jcem-47-1-168 (1978). · DOI
  8. Petit, A. et al. Presence of D2-dopamine receptors in human term placenta. J. Recept. Res. 10, 205–215. https://doi.org/10.3109/10799899009064666 (1990). · DOI
  9. Previc, F. H. Prenatal influences on brain dopamine and their relevance to the rising incidence of autism. Med. Hypotheses 68, 46–60. https://doi.org/10.1016/j.mehy.2006.06.041 (2007). · DOI
  10. Robinson, P. D., Schutz, C. K., Macciardi, F., White, B. N. & Holden, J. J. Genetically determined low maternal serum dopamine beta-hydroxylase levels and the etiology of autism spectrum disorders. Am. J. Med. Genet. 100, 30–36. https://doi.org/10.1002/ajmg.1187 (2001). · DOI
  11. Holzman, C. et al. Maternal catecholamine levels in midpregnancy and risk of preterm delivery. Am. J. Epidemiol. 170, 1014–1024. https://doi.org/10.1093/aje/kwp218 (2009). · DOI
  12. Jones, C. M. & Greiss, F. C. The effect of labor on maternal and fetal circulating catecholamines. Am. J. Obstet. Gynecol. 144, 149–153. https://doi.org/10.1016/0002-9378(82)90616-0 (1982). · DOI
  13. Möller, I. R. et al. Conformational dynamics of the human serotonin transporter during substrate and drug binding. Nat. Commun. 10, 1687. https://doi.org/10.1038/s41467-019-09675-z (2019). · DOI
  14. Mandela, P. & Ordway, G. A. The norepinephrine transporter and its regulation. J. Neurochem. 97, 310–333. https://doi.org/10.1111/j.1471-4159.2006.03717.x (2006). · DOI
  15. Borre, L., Andreassen, T. F., Shi, L., Weinstein, H. & Gether, U. The second sodium site in the dopamine transporter controls cation permeation and is regulated by chloride. J. Biol. Chem. 289, 25764–25773. https://doi.org/10.1074/jbc.M114.574269 (2014). · DOI
  16. Stamford, J. A., Kruk, Z. L. & Millar, J. Striatal dopamine terminals release serotonin after 5-HTP pretreatment: In vivo voltammetric data. Brain Res. 515, 173–180. https://doi.org/10.1016/0006-8993(90)90593-z (1990). · DOI
  17. Vizi, E. S., Zsilla, G., Caron, M. G. & Kiss, J. P. Uptake and release of norepinephrine by serotonergic terminals in norepinephrine transporter knock-out mice: Implications for the action of selective serotonin reuptake inhibitors. J. Neurosci. Off. J. Soc. Neurosci. 24, 7888–7894. https://doi.org/10.1523/JNEUROSCI.1506-04.2004 (2004). · DOI
  18. Gasser, P. J. Roles for the uptake(2) transporter OCT3 in regulation of dopaminergic neurotransmission and behavior. Neurochem. Int. 123, 46–49. https://doi.org/10.1016/j.neuint.2018.07.008 (2019). · DOI
  19. Miura, Y. et al. Characterization of murine polyspecific monoamine transporters. FEBS Open Bio 7, 237–248. https://doi.org/10.1002/2211-5463.12183 (2017). · DOI
  20. Ingebretsen, O. C. & Flatmark, T. Active and passive transport of dopamine in chromaffin granule ghosts isolated from bovine adrenal medulla. J. Biol. Chem. 254, 3833–3839 (1979). · DOI
  21. Scholze, P., Sitte, H. H. & Singer, E. A. Substantial loss of substrate by diffusion during uptake in HEK-293 cells expressing neurotransmitter transporters. Neurosci. Lett. 309, 173–176. https://doi.org/10.1016/s0304-3940(01)02058-4 (2001). · DOI
  22. Staud, F. & Karahoda, R. Trophoblast: The central unit of fetal growth, protection and programming. Int. J. Biochem. Cell Biol. 105, 35–40. https://doi.org/10.1016/j.biocel.2018.09.016 (2018). · DOI
  23. Prasad, P. D. et al. Functional expression of the plasma membrane serotonin transporter but not the vesicular monoamine transporter in human placental trophoblasts and choriocarcinoma cells. Placenta 17, 201–207 (1996). · DOI
  24. Bottalico, B. et al. Norepinephrine transporter (NET), serotonin transporter (SERT), vesicular monoamine transporter (VMAT2) and organic cation transporters (OCT1, 2 and EMT) in human placenta from pre-eclamptic and normotensive pregnancies. Placenta 25, 518–529. https://doi.org/10.1016/j.placenta.2003.10.017 (2004). · DOI · Paper page
  25. Shearman, L. P. & Meyer, J. S. Norepinephrine transporters in rat placenta labeled with [3H]nisoxetine. J. Pharmacol. Exp. Ther. 284, 736–743 (1998).
  26. Ramamoorthy, S. et al. Expression of a cocaine-sensitive norepinephrine transporter in the human placental syncytiotrophoblast. Biochemistry 32, 1346–1353. https://doi.org/10.1021/bi00056a021 (1993). · DOI
  27. Ramamoorthy, S., Leibach, F. H., Mahesh, V. B. & Ganapathy, V. Active transport of dopamine in human placental brush-border membrane vesicles. Am. J. Physiol. 262, C1189–C1196. https://doi.org/10.1152/ajpcell.1992.262.5.C1189 (1992). · DOI
  28. Karahoda, R. et al. Serotonin homeostasis in the materno-foetal interface at term: Role of transporters (SERT/SLC6A4 and OCT3/SLC22A3) and monoamine oxidase A (MAO-A) in uptake and degradation of serotonin by human and rat term placenta. Acta Physiol. 229, e13478. https://doi.org/10.1111/apha.13478 (2020). · DOI
  29. Sodha, R. J., Proegler, M. & Schneider, H. Transfer and metabolism of norepinephrine studied from maternal-to-fetal and fetal-to-maternal sides in the in vitro perfused human placental lobe. Am. J. Obstet. Gynecol. 148, 474–481. https://doi.org/10.1016/0002-9378(84)90729-4 (1984). · DOI · Paper page
  30. Koepsell, H. Organic cation transporters in health and disease. Pharmacol. Rev. 72, 253–319. https://doi.org/10.1124/pr.118.015578 (2020). · DOI
  31. Glazier, J. D., Jones, C. J. & Sibley, C. P. Purification and Na+ uptake by human placental microvillus membrane vesicles prepared by three different methods. Biochem. Biophys. Acta 945, 127–134 (1988). · DOI
  32. Farrugia, W., de Gooyer, T., Rice, G. E., Moseley, J. M. & Wlodek, M. E. Parathyroid hormone(1–34) and parathyroid hormone-related protein(1–34) stimulate calcium release from human syncytiotrophoblast basal membranes via a common receptor. J. Endocrinol. 166, 689–695 (2000). · DOI
  33. Horackova, H. et al. Effect of selected antidepressants on placental homeostasis of serotonin: Maternal and fetal perspectives. Pharmaceutics https://doi.org/10.3390/pharmaceutics13081306 (2021). · DOI
  34. Zhou, J. Norepinephrine transporter inhibitors and their therapeutic potential. Drugs Future 29, 1235–1244. https://doi.org/10.1358/dof.2004.029.12.855246 (2004). · DOI
  35. Berger, P., Elsworth, J. D., Arroyo, J. & Roth, R. H. Interaction of [3H]GBR 12935 and GBR 12909 with the dopamine uptake complex in nucleus accumbens. Eur. J. Pharmacol. 177, 91–94. https://doi.org/10.1016/0014-2999(90)90554-J (1990). · DOI
  36. Horton, R. E. et al. Decynium-22 enhances SSRI-induced antidepressant-like effects in mice: Uncovering novel targets to treat depression. J. Neurosci. Off. J. Soc. Neurosci. 33, 10534–10543. https://doi.org/10.1523/JNEUROSCI.5687-11.2013 (2013). · DOI
  37. Haka, M. S. & Kilbourn, M. R. Synthesis and regional mouse brain distribution of [11C]nisoxetine, a norepinephrine uptake inhibitor. Int. J. Rad. Appl. Instrum. B 16, 771–774. https://doi.org/10.1016/0883-2897(89)90160-8 (1989). · DOI
  38. Rothman, R. B. et al. Identification of a GBR12935 homolog, LR1111, which is over 4,000-fold selective for the dopamine transporter, relative to serotonin and norepinephrine transporters. Synapse 14, 34–39. https://doi.org/10.1002/syn.890140106 (1993). · DOI
  39. Bhat, S. et al. Handling of intracellular K+ determines voltage dependence of plasmalemmal monoamine transporter function. bioRxiv 2021.2003.2011.434931. https://doi.org/10.1101/2021.03.11.434931 (2021). · DOI
  40. Bzoskie, L., Blount, L., Kashiwai, K., Humme, J. & Padbury, J. F. The contribution of transporter-dependent uptake to fetal catecholamine clearance. Biol. Neonate 71, 102–110. https://doi.org/10.1159/000244403 (1997). · DOI
  41. Ganapathy, V., Ramamoorthy, S. & Leibach, F. H. Transport and metabolism of monoamines in the human placenta: A review. Placenta 14, 35–51. https://doi.org/10.1016/S0143-4004(05)80281-4 (1993). · DOI
  42. Watanabe, T., Matsuhashi, K. & Takayama, S. Placental and blood–brain barrier transfer following prenatal and postnatal exposures to neuroactive drugs: Relationship with partition coefficient and behavioral teratogenesis. Toxicol. Appl. Pharmacol. 105, 66–77. https://doi.org/10.1016/0041-008x(90)90359-3 (1990). · DOI
  43. Morgan, C. D., Sandler, M. & Panigel, M. Placental transfer of catecholamines in vitro and in vivo. Am. J. Obstet. Gynecol. 112, 1068–1075. https://doi.org/10.1016/0002-9378(72)90182-2 (1972). · DOI
  44. Coleman, J. A., Green, E. M. & Gouaux, E. X-ray structures and mechanism of the human serotonin transporter. Nature 532, 334–339. https://doi.org/10.1038/nature17629 (2016). · DOI · Paper page
  45. Pidathala, S., Mallela, A. K., Joseph, D. & Penmatsa, A. Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters. Nat. Commun. 12, 2199. https://doi.org/10.1038/s41467-021-22385-9 (2021). · DOI
  46. Larsen, M. B. et al. Dopamine transport by the serotonin transporter: A mechanistically distinct mode of substrate translocation. J. Neurosci. 31, 6605–6615. https://doi.org/10.1523/jneurosci.0576-11.2011 (2011). · DOI
  47. Jansson, T. & Illsley, N. P. Osmotic water permeabilities of human placental microvillous and basal membranes. J. Membr. Biol. 132, 147–155. https://doi.org/10.1007/bf00239004 (1993). · DOI
  48. Bzoskie, L. et al. Placental norepinephrine clearance: In vivo measurement and physiological role. Am. J. Physiol. 269, E145–E149. https://doi.org/10.1152/ajpendo.1995.269.1.E145 (1995). · DOI
  49. Cengiz, H. et al. Plasma serotonin levels are elevated in pregnant women with hyperemesis gravidarum. Arch. Gynecol. Obstet. 291, 1271–1276. https://doi.org/10.1007/s00404-014-3572-2 (2015). · DOI
  50. Carrasco, G. et al. Plasma and platelet concentration and platelet uptake of serotonin in normal and pre-eclamptic pregnancies. Life Sci. 62, 1323–1332. https://doi.org/10.1016/S0024-3205(98)00066-6 (1998). · DOI
  51. Khatun, S. et al. Increased concentrations of plasma epinephrine and norepinephrine in patients with eclampsia. Eur. J. Obstet. Gynecol. Reprod. Biol. 69, 61–67. https://doi.org/10.1016/0301-2115(95)02511-1 (1996). · DOI
  52. Middelkoop, C. M., Dekker, G. A., Kraayenbrink, A. A. & Popp-Snijders, C. Platelet-poor plasma serotonin in normal and preeclamptic pregnancy. Clin. Chem. 39, 1675–1678. https://doi.org/10.1093/clinchem/39.8.1675 (1993). · DOI
  53. Greenwood, S. L. & Sibley, C. P. In vitro methods for studying human placental amino acid transport placental villous fragments. Methods Mol. Med. 122, 253–264 (2006).

Metadata

Authors
Horackova, H., Karahoda, R., Vachalova, V., Turkova, H., Abad, C., & Staud, F.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2022-07-08
Volume
12
Issue
1
ISSN
2045-2322
DOI
10.1038/s41598-022-15790-7
Cited by
24
References
4
Language
en
Licence
Funders
  • Grantová Agentura České Republiky (20/13017S)
  • Charles University Grant Schemes (CZ.02.2.69/0.0/0.0/19_073/0016935)
  • Grant Agency of Charles University (SVV 260414)

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