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The pro\u2010resolving lipid mediator resolvin D2 (RvD2) biosynthesized from an omega 3 fatty acid actively terminates inflammation and regulates mucin secretion from conjunctival goblet cells. Our objective was to determine which Ca<jats:sup>2+<\/jats:sup>\u2010dependent signaling pathways RvD2 uses to stimulate conjunctival goblet cell function (CGC). We hypothesize that RvD2 activates multiple intracellular Ca<jats:sup>2+<\/jats:sup> signaling pathways to stimulate CGC secretion. Rat and human CGCs were cultured from conjunctival explants. The amount of RvD2 receptor GPR18\/DRV2 message and protein were determined. The intracellular concentration of Ca<jats:sup>2+<\/jats:sup> ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) was measured in CGCs using a fluorescent Ca<jats:sup>2+<\/jats:sup> dye and mucin secretion was determined by measuring protein secretion enzymatically with a lectin. Goblet cells were incubated with signaling pathway inhibitors before stimulation with RvD2 and [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> or secretion was measured. In rat and human CGCs RvD2 receptor and in rat CGCs IP<jats:sub>3<\/jats:sub> (a molecule that releases Ca<jats:sup>2+<\/jats:sup> from intracellular organelles) receptors 1\u20133 were detected. In both species of CGC RvD2 increased [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> similarly to RvD1. In rat CGCs, the increase in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> and secretion stimulated by RvD2 was significantly blocked by inhibitors to phospholipase (PL\u2010) C and IP<jats:sub>3<\/jats:sub>\u2010receptor, but not protein kinase C. Increase in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> was blocked by the PLD inhibitor, but not the PLA<jats:sub>2<\/jats:sub> inhibitor. Secretion was blocked by PLA<jats:sub>2<\/jats:sub> inhibitor, but not the PLD inhibitor. An inhibitor of the epidermal growth factor receptor blocked the increase in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> by RvD2 in both species of CGCs. In CGCs RvD2 activates multiple intracellular signaling pathways that are Ca<jats:sup>2+<\/jats:sup>\u2010dependent, along with one Ca<jats:sup>2+<\/jats:sup>\u2010independent and one cAMP\/protein kinase A\u2010dependent pathway. Activation of these pathways stimulate mucin secretion from rat and human CGCs into the tear film contributing to ocular surface homeostasis and health.<\/jats:p>","DOI":"10.1002\/jcp.30854","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T12:14:16Z","timestamp":1662466456000},"page":"3816-3833","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Resolvin D2 uses multiple Ca<sup>2+<\/sup>\u2010dependent signaling pathways to stimulate mucin secretion in rat and human conjunctival goblet cells"],"prefix":"10.1002","volume":"237","author":[{"given":"Nora","family":"Botten","sequence":"first","affiliation":[{"name":"Schepens Eye Research Institute, Massachusetts Eye and Ear Harvard Medical School Boston Massachusetts USA"},{"name":"Department of Ophthalmology Harvard Medical School Boston Massachusetts USA"},{"name":"Department of Medical Biochemistry Oslo University Hospital Oslo 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