Intermediate Conductance Ca2+-Activated K+ Channels Modulate Human Placental Trophoblast Syncytialization
Open accessAbstract
Regulation of human placental syncytiotrophoblast renewal by cytotrophoblast migration, aggregation/fusion and differentiation is essential for successful pregnancy. In several tissues, these events are regulated by intermediate conductance Ca2+-activated K+ channels (IKCa), in part through their ability to regulate cell volume. We used cytotrophoblasts in primary culture to test the hypotheses that IKCa participate in the formation of multinucleated syncytiotrophoblast and in syncytiotrophoblast volume homeostasis. Cytotrophoblasts were isolated from normal term placentas and cultured for 66 h. This preparation recreates syncytiotrophoblast formation in vivo, as mononucleate cells (15 h) fuse into multinucleate syncytia (66 h) concomitant with elevated secretion of human chorionic gonadotropin (hCG). Cells were treated with the IKCa inhibitor TRAM-34 (10 µM) or activator DCEBIO (100 µM). Culture medium was collected to measure hCG secretion and cells fixed for immunofluorescence with anti-IKCa and anti-desmoplakin antibodies to assess IKCa expression and multinucleation respectively. K+ channel activity was assessed by measuring 86Rb efflux at 66 h. IKCa immunostaining was evident in nucleus, cytoplasm and surface of mono- and multinucleate cells. DCEBIO increased 86Rb efflux 8.3-fold above control and this was inhibited by TRAM-34 (85%; p<0.0001). Cytotrophoblast multinucleation increased 12-fold (p<0.05) and hCG secretion 20-fold (p<0.05), between 15 and 66 h. Compared to controls, DCEBIO reduced multinucleation by 42% (p<0.05) and hCG secretion by 80% (p<0.05). TRAM-34 alone did not affect cytotrophoblast multinucleation or hCG secretion. Hyposmotic solution increased 86Rb efflux 3.8-fold (p<0.0001). This effect was dependent on extracellular Ca2+, inhibited by TRAM-34 and 100 nM charybdotoxin (85% (p<0.0001) and 43% respectively) but unaffected by 100 nM apamin. In conclusion, IKCa are expressed in cytotrophoblasts and their activation inhibits the formation of multinucleated cells in vitro. IKCa are stimulated by syncytiotrophoblast swelling implicating a role in syncytiotrophoblast volume homeostasis. Inappropriate activation of IKCa in pathophysiological conditions could compromise syncytiotrophoblast turnover and volume homeostasis in pregnancy disease.
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Ca2+-activated K+ channels have recently been demonstrated to be important for trophoblast syncytialization and for syncytial volume homeostasis.
“In addition, Ca 2+ -activated K + channels have recently been demonstrated to be important for trophoblast syncytialization and for syncytial volume homeostasis (145).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [145]
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Placental Origins of Chronic Disease
Burton, G. J., Fowden, A. L., & Thornburg, K. L. (2016) · Physiological Reviews · doi:10.1152/physrev.00029.2015 · Cited by 717 · see citing works
- Authors
- Díaz, P., Wood, A. M., Sibley, C. P., & Greenwood, S. L.
- Affiliations
- National Health Service (GB)
- Corresponding author
- Díaz, Paula
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-03-03
- Volume
- 9
- Issue
- 3
- Pages
- e90961
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3940956
- OpenAlex
- W2030868212
- Cited by
- 18
- References
- 76
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 1 · 2022: 2 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 3 · 2015: 4 · 2014: 1
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Action Medical Research
- Tommy's
- Comisión Nacional de Investigación Científica y Tecnológica
- Topics
- Health Sciences › Medicine › Obstetrics and Gynecology › Pregnancy and preeclampsia studies
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Keywords
- intermediate-conductance calcium-activated potassium channel, syncytiotrophoblast formation, trophoblast syncytialization, human chorionic gonadotropin secretion, cell volume regulation, potassium efflux, TRAM-34, charybdotoxin, hypoosmotic stress
- MeSH terms
- Analysis of Variance, Benzimidazoles, Biological Transport, Cell Fusion, Female, Fluorescent Antibody Technique, Chorionic Gonadotropin, Humans, Placenta, Pregnancy, Pyrazoles, Rubidium Radioisotopes, Trophoblasts, Linear Models, Cell Culture Techniques, Potassium Channels, Calcium-Activated
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