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

Abstract

Purpose: : The inositol 1,4,5-trisphosphate receptor (IP3R) is a Ca²⁺ release channel located on the endoplasmic reticulum, and consists of three distinct subtypes. No role of IP3R in tear secretion has been reported. We examined the function of IP3Rs and Ca²⁺signaling in tear secretion in various IP3R gene knockout mice (IP3RKO).

Methods: : We used IP3RKO and wild type (WT) mice in all the experiments. Tear secretion was measured after treatment with 3mg/kg pilocarpine. Pathological and immunohistchemical analyses were performed to evaluate lacrimal gland tissue sections using a light and electron microscopy. To examine the Ca²⁺ signaling induced by cholinergic stimulation of the lacrimal gland, a Ca²⁺ sensing dye (Fura-2) was used to measure ratiometrically the Ca²⁺ in lacrimal gland acinar cells from IP3RKO and WT mice.

Results: : Mice that were double deficient, for IP3R2 and IP3R3 (IP3R2/3KO) showed significant decrease of pilocarpine-stimulated tear secretion compared with WT mice. Moreover, the lacrimal gland acinar cells of the IP3R2/3KO mice showed severely impaired Ca2+ signaling. Lacrimal gland dysfunction caused an abnormal accumulation of secretory granules in the acinar epithelia. In addition, degeneration of lacrimal gland induced the infiltration of inflammatory mononuclear cells, and an increased expression of the proinflammatory cytokines such as TNF- and IL-6 in the lacrimal gland of IP3R2/3 mice.

Conclusions: : We concluded that IP3R and Ca²⁺ signaling play key roles in tear secretion. In addition, the decreased tear secretion and an increase in inflammatory cells in these mice were similar to those of Sjögren’s syndrome, suggesting that IP3R2/3KO mice may be useful as a new animal model for Sjögren’s syndrome.

Keywords: lacrimal gland • acetylcholine • inflammation