title: Regulatory Action of Calcium Ion on Cyclic AMP-Enhanced Expression of Implantation-Related Factors in Human Endometrial Cells.
abstract: 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.
authors.affiliation: Department of Endocrine and Neural Pharmacology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan; Laboratory of Theriogenology and Animal Breeding, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo, 113-8657, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kusama
authors.affiliation: Department of Endocrine and Neural Pharmacology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Mikihiro
authors.initials: M
authors.lastname: Yoshie
authors.affiliation: Department of Endocrine and Neural Pharmacology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Laboratory of Theriogenology and Animal Breeding, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo, 113-8657, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Imakawa
authors.affiliation: Department of Obstetrics and Gynecology, Tokyo Medical University, 6-7-1 Nishishinjuku, Tokyo, 160-0023, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Isaka
authors.affiliation: Department of Endocrine and Neural Pharmacology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Tachikawa
mesh_terms: D000408:Alamethicin / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002460:Cell Line; D002614:Chelating Agents / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D003620:Dantrolene / Q000494:pharmacology; D003656:Decidua / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D010064:Embryo Implantation / Q000187:drug effects; D004717:Endometrium / Q000166:cytology*; D005260:Female; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D007477:Ions; D008954:Models, Biological; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D015415:Biomarkers; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002614:Chelating Agents; D007476:Ionophores; D007477:Ions; D019837:Ryanodine Receptor Calcium Release Channel; D005576:Colforsin; D000408:Alamethicin; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; D003620:Dantrolene; D015232:Dinoprostone; D002118:Calcium