Role of Inositol 1, 4, 5, -Triphosphate Receptors and Ca2+ Signaling in Tear Secretion

Abstract

Purpose: : 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).

Methods: : 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).

Results: : 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.

Conclusions: : 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.

Keywords: lacrimal gland • inflammation • acetylcholine