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G Protein-Coupled Estrogen Receptor Inhibits the P2Y Receptor-Mediated Ca2+ Signaling Pathway in Human Airway Epithelia

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G Protein-Coupled Estrogen Receptor Inhibits the P2Y Receptor-Mediated Ca2+ Signaling Pathway in Human Airway Epithelia Pflugers Arch - Eur J Physiol DOI 10.1007/s00424-016-1840-7 SIGNALING AND CELL PHYSIOLOGY G protein-coupled estrogen receptor inhibits the P2Y receptor-mediated Ca2+ signaling pathway in human airway epithelia Yuan Hao1 & Alison W. Chow1 & Wallace C. Yip 1 & Chi H. Li1 & Tai F. Wan 1 & Benjamin C. Tong2 & King H. Cheung2 & Wood Y. Chan 1 & Yangchao Chen 1 & Christopher H. Cheng1 & Wing H. Ko1 Received: 21 January 2016 /Revised: 11 May 2016 /Accepted: 22 May 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract P2Y receptor activation causes the release of in- inhibitory effects of G1 or E2 on P2Y receptor-mediated flammatory cytokines in the bronchial epithelium, whereas Ca2+ mobilization and cytokine secretion were due to G protein-coupled estrogen receptor (GPER), a novel estrogen GPER-mediated activation of a cAMP-dependent PKA path- (E2) receptor, may play an anti-inflammatory role in this pro- way. This study has reported, for the first time, the expression cess. We investigated the cellular mechanisms underlying the and function of GPER as an anti-inflammatory component in inhibitory effect of GPER activation on the P2Y receptor- human bronchial epithelia, which may mediate through its mediated Ca2+ signaling pathway and cytokine production in opposing effects on the pro‐inflammatory pathway activated airway epithelia. Expression of GPER in primary human by the P2Y receptors in inflamed airway epithelia. bronchial epithelial (HBE) or 16HBE14o- cells was con- firmed on both the mRNA and protein levels. Stimulation of Keywords GPER . P2Y receptor signaling pathway . Human HBE or 16HBE14o- cells with E2 or G1, a specific agonist of . 2+ bronchial epithelial cells Calcium signaling cAMP GPER, attenuated the nucleotide-evoked increases in [Ca ]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 Introduction adenosine 5′-(γ-thio)triphosphate (ATPγS). G1 stimulated a real-time increase in cAMP levels in 16HBE14o- cells, which Estrogen (E2) is an important hormone that protects the lungs could be inhibited by adenylyl cyclase inhibitors. The inhibi- from inflammatory damage. Clinical observations suggested that reduced E levels were associated with greater risks of lung pa- tory effects of E2 or G1 on P2Y receptor-induced increases in 2 Ca2+ were reversed by treating the cells with a protein kinase thologies in menopausal women [19, 36]. However, the detailed A (PKA) inhibitor. These results demonstrated that the anti-inflammatory role played by E2 and its pathophysiological mechanism are still unknown. In addition to the classical nuclear hormone receptors, ERα and ERβ, a novel E2 receptor and a G Electronic supplementary material The online version of this article protein-coupled estrogen receptor (GPER), were recently identi- (doi:10.1007/s00424-016-1840-7) contains supplementary material, fied [35, 43]. Despite the accumulating body of evidence indicat- which is available to authorized users. ing that the rapid, nongenomic actions of E2 observed in the epi- * Christopher H. Cheng thelia are mediated via GPER, few studies have investigated the [email protected] specific role of GPER in inflammatory airway diseases [31, 32]. * Wing H. Ko Extracellular nucleotide release and the subsequent activa- [email protected] tion of P2Y receptors have been implicated in the pathogene- sis of several inflammatory lung disorders, such as asthma 1 School of Biomedical Sciences, The Chinese University of Hong [28]. During airway inflammation, damage to the surface ep- Kong, Shatin, Hong Kong ithelium is due to the secretion of eosinophil-derived, highly 2 School of Biomedical Sciences, The University of Hong Kong, toxic, cationic proteins, such as major basic protein (MBP). Pokfulam, Hong Kong Our recent study demonstrated that when human bronchial Pflugers Arch - Eur J Physiol surface epithelia are chemically damaged by poly-L-arginine Transcription Supermix (Bio-Rad Laboratories, Hercules, as a surrogate of MBP [10], nucleotides, such as ATP and USA). Reverse transcription PCR (RT-PCR) was performed UDP, are released into the extracellular medium. The extracel- with TaKaRa Taq™ DNA polymerase. Real-time PCR was lular nucleotides then activate cell surface P2Y receptors to performed with an Applied Biosystems Power SYBR Green release two proinflammatory cytokines, interleukin (IL)-6 and PCR Master Mix (Invitrogen) on a ViiA™ 7real-timePCR IL-8, via a Ca2+-dependent process [20]. system. GPER primer sequences were as follows: forward To the best of our knowledge, no reports have determined primer, 5′-TCTACACCATCTTCCTCTTCC-3′; and reverse whether GPER is expressed in airway epithelia or whether primer, 5′-GTAGCGGTCGAAGCTCATCC-3′.TheRT- GPER plays a role in the regulation of P2Y receptor- PCR products were characterized using 2 % agarose gel elec- mediated Ca2+ signaling and cytokine secretion in airway ep- trophoresis. Relative expression of GPER was normalized to ithelia. Therefore, we examined the expression of GPER and GAPDH and determined with the Pfaffl method [30]. Each its subcellular localization in human bronchial epithelia. We run of PCR included a nontemplate control and a sample also characterized the cross talk between the GPER and P2Y without reverse transcriptase. receptor signaling pathways and its implications on the anti- inflammatory role of GPER. Western blotting Western blotting was performed as described previously [10]. Materials and methods Cells grown in culture dishes were lysed on ice in Cytobuster™ Protein Extraction Reagent (Merck Millipore, Solutions and chemicals Billerica, USA), supplemented with a protease inhibitor cock- tail (no. 78429, Thermofisher Scientific, Waltham, USA) and Krebs-Henseleit (KH) solution and the nominally Ca2+-free a phosphatase inhibitor cocktail (Merck Millipore). Protein solution were prepared as previously described [24]. samples (20 μg per lane) were transferred to polyvinylidene Membrane permeant acetoxymethyl (AM) ester forms of fluoride (PVDF) membranes (Immobilon-P, Merck Millipore) Fura-2 and Pluronic F127 were obtained from Invitrogen and immunoblotted with GPER rabbit polyclonal antibody (Carlsbad, USA). Uridine 5′-triphosphate (UTP), uridine 5′- (N-15)-R (1:500; Santa Cruz Biotechnology, Santa Cruz, diphosphate (UDP), adenosine 5′-(γ-thio)triphosphate USA). Blocking peptide (sc-38525 P, Santa Cruz (ATPγS), forskolin, poly-L-arginine hydrochloride, SQ Biotechnology) was used for GPER antibody preabsorption, 22536, U73122, E2, and G1 were obtained from Sigma- and mouse monoclonal antibody to GAPDH was used as a load- Aldrich (St. Louis, USA). G15 was obtained from Tocris ing control. All blots were developed using an enhanced chemi- (Bristol, UK). H89 dihydrochloride and MDL 12330A were luminescence detection system (Merck Millipore). The apparent obtained from Calbiochem (La Jolla, USA). All other general molecular masses were calculated using prestained sodium dode- laboratory reagents were obtained from Sigma-Aldrich, and cyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) all cell culture reagents were obtained from Invitrogen. midrange protein markers (no. HM0671, Hou-Bio Life Technologies, Hong Kong). Cell culture Immunofluorescence microscopy The 16HBE14o- cell line was maintained in minimum essen- tial medium (MEM) supplemented with 10 % fetal bovine 16HBE14o- or primary HBE cells grown on coverslips in serum, 1 % penicillin/streptomycin, and 1 % glutamine four-well plates were rinsed with phosphate-buffered saline (Invitrogen, Carlsbad, CA) and cultured as described previ- (PBS) and fixed in 4 % paraformaldehyde for 10 min at room ously [47]. In some experiments, MEM with no phenol red temperature. Cells were blocked using PBS with 10 % normal (Invitrogen) was applied. Primary HBE cells were obtained horse serum and 0.1 % Triton X-100 for 1 h and incubated from ScienCell Research Laboratories (Carlsbad, USA) and with GPER (N-15)-R rabbit polyclonal antibody (1:60; sc- cultured using Bronchial Epithelial Cell Medium (ScienCell 48525-R, Santa Cruz Biotechnology) overnight at 4 °C [13]. Research Laboratories) following the commercial protocol After washing, Alexa Fluor® 488 donkey anti-rabbit IgG (H+ described previously [20]. L) was added (1:300, Thermofisher Scientific, Waltham, USA). The coverslips were mounted using mounting medium RNA extraction, reverse transcription PCR, and real-time with 1.5 μg/ml 4′,6-diamidino-2-phenylindole (DAPI). PCR Images were captured using a FluoView™-FV1000 confocal microscope (Olympus, Center Valley, USA). In some experi- Total RNA was extracted with TRIzol Reagent (Invitrogen) ments, cells were co-incubated with purified mouse anti-E- and reverse transcribed to cDNA using iScript™ Reverse cadherin (1:200; no. 610181, BD Biosciences, Heidelberg, Pflugers Arch - Eur J Physiol Germany), purified mouse anti-GM130 (1:200; no. 610823, (100 nM) or G1 (10 nM) for 10 min. Then 1-mM MnCl2 was BD Biosciences), or KDEL antibody (1:500; NBP1-97469, addedinperfusionsolutiontoobservetheextentofMn2+ entry. Novus Biologicals, Littleton, USA). Alexa Fluor® 555 don- TherateofMn2+ quenching was assessed by measuring the key anti-rabbit IgG was used for visualization (1:400, change of slope of Fura-2 fluorescence decrease before and Thermofisher Scientific). For the negative control group, after the addition of Mn2+ application (using Originlab 8 soft- GPER antibodies
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