G protein-coupled estrogen receptor inhibits the P2Y receptor-mediated Ca2+ signaling pathway in human airway epithelia

Yuan Hao, Alison W. Chow, Wallace C. Yip, Chi H. Li, Tai F. Wan, Benjamin C. Tong, King H. Cheung, Wood Y. Chan, Yangchao Chen, Christopher H. Cheng*, Wing H. Ko*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

8 Citations (Scopus)

Abstract

P2Y receptor activation causes the release of inflammatory cytokines in the bronchial epithelium, whereas G protein-coupled estrogen receptor (GPER), a novel estrogen (E2) receptor, may play an anti-inflammatory role in this process. We investigated the cellular mechanisms underlying the inhibitory effect of GPER activation on the P2Y receptor-mediated Ca2+ signaling pathway and cytokine production in airway epithelia. Expression of GPER in primary human bronchial epithelial (HBE) or 16HBE14o- cells was confirmed on both the mRNA and protein levels. Stimulation of HBE or 16HBE14o- cells with E2 or G1, a specific agonist of GPER, attenuated the nucleotide-evoked increases in [Ca2+]i, whereas this effect was reversed by G15, a GPER-specific antagonist. G1 inhibited the secretion of two proinflammatory cytokines, interleukin (IL)-6 and IL-8, in cells stimulated by adenosine 5′-(γ-thio)triphosphate (ATPγS). G1 stimulated a real-time increase in cAMP levels in 16HBE14o- cells, which could be inhibited by adenylyl cyclase inhibitors. The inhibitory effects of E2 or G1 on P2Y receptor-induced increases in Ca2+ were reversed by treating the cells with a protein kinase A (PKA) inhibitor. These results demonstrated that the inhibitory effects of G1 or E2 on P2Y receptor-mediated Ca2+ mobilization and cytokine secretion were due to GPER-mediated activation of a cAMP-dependent PKA pathway. This study has reported, for the first time, the expression and function of GPER as an anti-inflammatory component in human bronchial epithelia, which may mediate through its opposing effects on the pro‐inflammatory pathway activated by the P2Y receptors in inflamed airway epithelia.

Original languageEnglish
Pages (from-to)1489-1503
Number of pages15
JournalPflugers Archiv European Journal of Physiology
Volume468
Issue number8
DOIs
Publication statusPublished - Aug 2016
Externally publishedYes

User-Defined Keywords

  • GPER
  • P2Y receptor signaling pathway
  • Human bronchial epithelial cells
  • Calcium signaling
  • cAMP

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