Regulatory Action of Calcium Ion on Cyclic AMP-Enhanced Expression of Implantation-Related Factors in Human Endometrial Cells

• Published in: PloS one Vol. 10; no. 7; p. e0132017
• Main Authors: Kusama, Kazuya, Yoshie, Mikihiro, Tamura, Kazuhiro, Imakawa, Kazuhiko, Isaka, Keiichi, Tachikawa, Eiichi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.07.2015; Public Library of Science (PLoS)
• Subjects: Alamethicin - pharmacology; Biomarkers - metabolism; Breeding of animals; Calcium; Calcium (intracellular); Calcium - pharmacology; Calcium Channel Blockers - pharmacology; Calcium channels; Calcium channels (L-type); Calcium channels (voltage-gated); Calcium Channels, L-Type - metabolism; Calcium influx; Calcium ionophores; Calcium signalling; Cell Line; Chelating Agents - pharmacology; Colforsin - pharmacology; Cyclic AMP; Cyclic AMP - pharmacology; Cyclooxygenase 2 - metabolism; Cyclooxygenase-2; Dantrolene - pharmacology; Decidua; Decidua - drug effects; Decidua - metabolism; Dinoprostone - biosynthesis; Embryo Implantation - drug effects; Embryos; Endometrium; Endometrium - cytology; Epithelial cells; Female; Forskolin; Gene expression; Humans; Implantation; Insulin-like growth factor-binding protein 1; Insulin-like growth factors; Intracellular; Intracellular signalling; Ionomycin; Ionophores; Ionophores - pharmacology; Ions; Kinases; Laboratories; Medical research; Menstruation; Models, Biological; Nifedipine; Pharmacology; Pharmacy; Physiology; Pituitary hormones; Prolactin; Prostaglandin E2; Protein binding; Proteins; Ryanodine Receptor Calcium Release Channel - metabolism; Signal transduction; Stromal Cells - drug effects; Stromal Cells - metabolism; Transcription; Variation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0132017

Decidualization of human endometrial stroma and gland development is mediated through cyclic AMP (cAMP), but the role of intracellular calcium ion (Ca2+) on cAMP mediated-signaling in human endometrial stroma and glandular epithelia has not been well-characterized. The present study was designed to investigate the role of intracellular Ca2+ on cAMP mediated-decidualization and gland maturation events, which can be identified by the up-regulation of prolactin and IGF-binding protein (IGFBP)1 in human endometrial stromal cells (ESCs), and cyclooxygenase 2 (COX2) and prostaglandin E2 (PGE2) and glandular epithelial EM-1 cells. Increases in decidual prolactin and IGFBP-1 transcript levels, induced by cAMP-elevating agents forskolin or dibutyryl cyclic AMP, were inhibited by Ca2+ influx into ESCs with Ca2+ ionophores (alamethicin, ionomycin) in a dose-dependent manner. Conversely, inhibitors of Ca2+ influx through L-type voltage-dependent Ca2+ channel (VDCC), nifedipine and verapamil, enhanced the decidual gene expression. Furthermore, dantrolene, an inhibitor of Ca2+ release from the intracellular Ca2+ store, up-regulated prolactin and IGFBP-1 expression. Ca2+ ionophores decreased intracellular cAMP concentrations, whereas nifedipine, verapamil or dantrolene increased cAMP concentrations in ESCs. In glandular epithelial cells, similar responses in COX2 expression and PGE2 production were found when intracellular cAMP levels were up-regulated by decreases in Ca2+ concentrations. Thus, a marked decrease in cytosolic Ca2+ levels caused the elevation of cAMP concentrations, resulting in enhanced expression of implantation-related factors including decidual markers. These findings suggest that fluctuation in cytosolic Ca2+ concentrations alters intracellular cAMP levels, which then regulate differentiation of endometrial stromal and glandular epithelial cells.