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Histamine is a key inflammatory mediator known to trigger vasodilation and vessel hyperpermeability upon binding to its receptors and evoking intracellular Ca<jats:sup>2+<\/jats:sup>([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) dynamics for downstream signal transductions. However, the exact molecular mechanisms beneath the [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>dynamics and the downstream cellular effects have not been elucidated in the lymphatic system. Here, we show that Ca<jats:sup>2+<\/jats:sup>release-activated Ca<jats:sup>2+<\/jats:sup>(CRAC) channels, formed by Orai1 and stromal interaction molecule 1 (STIM1) proteins, are required for the histamine-elicited Ca<jats:sup>2+<\/jats:sup>signaling in human dermal lymphatic endothelial cells (HDLECs). Blockers or antagonists against CRAC channels, phospholipase C, and H<jats:sub>1<\/jats:sub>R receptors can all significantly diminish the histamine-evoked [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>dynamics in lymphatic endothelial cells (LECs), while short interfering RNA-mediated knockdown of endogenous Orai1 or STIM1 also abolished the Ca<jats:sup>2+<\/jats:sup>entry upon histamine stimulation in LECs. Furthermore, we find that histamine compromises the lymphatic endothelial barrier function by increasing the intercellular permeability and disrupting vascular endothelial-cadherin integrity, which is remarkably attenuated by CRAC channel blockers. Additionally, the upregulated expression of inflammatory cytokines, IL-6 and IL-8, after histamine stimulation was abolished by silencing Orai1 or STIM1 with RNAi in LECs. Taken together, our data demonstrated the essential role of CRAC channels in mediating the [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>signaling and downstream endothelial barrier and inflammatory functions induced by histamine in the LECs, suggesting a promising potential to relieve histamine-triggered vascular leakage and inflammatory disorders in the lymphatics by targeting CRAC channel functions.<\/jats:p>","DOI":"10.1152\/ajpheart.00544.2019","type":"journal-article","created":{"date-parts":[[2020,4,10]],"date-time":"2020-04-10T17:57:50Z","timestamp":1586541470000},"page":"H1283-H1295","source":"Crossref","is-referenced-by-count":15,"title":["Ca<sup>2+<\/sup>release-activated Ca<sup>2+<\/sup>channels are responsible for histamine-induced Ca<sup>2+<\/sup>entry, permeability increase, and interleukin synthesis in lymphatic endothelial cells"],"prefix":"10.1152","volume":"318","author":[{"given":"Hongjiang","family":"Si","sequence":"first","affiliation":[{"name":"Department of 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