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T. Inaba, C. Hisatsune, Y. Sasaki, Y. Ogawa, K. Mikoshiba, K. Tsubota; Role of Inositol 1, 4, 5, -Triphosphate Receptors and Ca2+ Signaling in Tear Secretion. Invest. Ophthalmol. Vis. Sci. 2010;51(13):4168.
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© ARVO (1962-2015); The Authors (2016-present)
Inositol 1,4,5, trisphosphate receptor (IP3R) is a Ca2+ release channel that localized on the endoplasm reticulum. IP3Rs consist of three distinct subtypes. However, the relation between tear secretion and IP3R has not been reported. We examined the role of IP3Rs and Ca2+signaling in tear secretion by using various IP3R gene knockout mice (IP3RKO).
We used IP3RKO and wild-type mice (WT) in all experiments. Measurement of tear secretion was performed after 3 mg/kg pilocarpine treatment. Pathological and immunohistchemical analyses were performed to evaluate lacrimal gland tissue sections using a light microscopy and an electron microscopy. In order to examine Ca2+ signaling induced by cholinergic stimulation in lacrimal gland, the Ca2+ in lacrimal gland acinar cells from IP3RKO and WT were measured ratiometrically using Ca2+ -sensing dye (Fura-2).
Double deficient mouse of IP3R2 and IP3R3 (IP3R2/3KO) gene showed significant decrease of pilocarpine-stimulated tear secretion compared with WT. In addition, tear deficiency in IP3R2/3KO was caused by severely impaired Ca2+ signaling in the lacrimal gland acinar cells. Lacrimal gland dysfunction caused abnormal accumulation of secretory granules in the acinar epithelia. Additionally, degeneration of lacrimal gland induced the infiltration of inflammatory mononuclear cells in IP3R2/3, and expression of the proinflammatory cytokines were increased in the lacrimal gland such as TNF-α and IL-6.
We concluded that IP3R and Ca2+ signaling are key molecules for tear secretion. Our results suggest that IP3R2/3KO may become a novel Sjögren’s syndrome model.
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