Tear secretion is important as it supplies water to the ocular surface and keeps eyes moist. Both the parasympathetic and sympathetic pathways contribute to tear secretion. Although intracellular Ca2+ elevation in the acinar cells of lacrimal glands is a crucial event for tear secretion in both the pathways, the Ca2+ channel, which is responsible for the Ca2+ elevation in the sympathetic pathway, has not been sufficiently analyzed. In this study, we examined tear secretion in mice lacking the inositol 1,4,5-trisphosphate receptor (IP3R) types 2 and 3 (Itpr2？/？;Itpr3？/？double-knockout mice). We found that tear secretion in both the parasympathetic and sympathetic pathways was abolished in Itpr2？/？;Itpr3？/？ mice. Intracellular Ca2+ elevation in lacrimal acinar cells after acetylcholine and epinephrine stimulation was abolished in Itpr2？/？;Itpr3？/？ mice. Consequently, Itpr2？/？;Itpr3？/？ mice exhibited keratoconjunctival alteration and corneal epithelial barrier disruption. Inflammatory cell infiltration into the lacrimal glands and elevation of serum autoantibodies, a representative marker for Sj？gren’s syndrome (SS) in humans, were also detected in older Itpr2？/？;Itpr3？/？ mice. These results suggested that IP3Rs are essential for tear secretion in both parasympathetic and sympathetic pathways and that Itpr2？/？;Itpr3？/？ mice could be a new dry eye mouse model with symptoms that mimic those of SS.
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