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

Kazuya Kusama, Mikihiro Yoshie, Kazuhiro Tamura, Kazuhiko Imakawa, Keiichi Isaka, Eiichi Tachikawa
In: PLOS ONE · 2015 · vol. 10(7) , pp. e0132017 · doi:10.1371/journal.pone.0132017 · PMID:26161798 · PMC4498924 · W1492812051
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⚙ AI-generated summary by claude@2026-06, 2026-06-09 ⓘ

Intracellular calcium ion concentrations inversely regulate cyclic AMP levels, thereby modulating the expression of implantation-related factors in human endometrial stromal and glandular epithelial cells.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-09 ⓘ

Kusama et al. investigated how intracellular Ca2+ modulates cAMP-driven decidualization and gland maturation in human endometrial stromal cells (ESCs) and a human glandular epithelial cell line (EM-1) using cAMP-elevating agents (forskolin, db-cAMP) and Ca2+ modulators. They found that Ca2+ influx into ESCs via Ca2+ ionophores (alamethicin, ionomycin) dose-dependently inhibited cAMP-induced up-regulation of decidual markers (prolactin, IGFBP-1 transcript levels) and that blocking Ca2+ influx through L-type VDCC with nifedipine or verapamil enhanced expression; the Ca2+ store release inhibitor dantrolene also increased these markers, coinciding with decreased versus increased intracellular cAMP levels. In EM-1 cells, cAMP up-regulation driven by lower Ca2+ concentrations similarly increased COX2 expression and PGE2 production. The study used in vitro human cell models and primary ESCs derived from women undergoing endometriosis surgery, which is a limited representation of in vivo endometrial physiology. This paper is centrally about endometriosis and adenomyosis as it uses eutopic endometrial tissue from women undergoing endometriosis surgery to study Ca2+-cAMP signaling that regulates implantation-related differentiation of endometrial stromal and glandular epithelial cells.

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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.

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