Mice lacking inositol 1,4,5-trisphosphate receptors exhibit dry eye

PLoS One. 2014 Jun 5;9(6):e99205. doi: 10.1371/journal.pone.0099205. eCollection 2014.


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 Sjögren'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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / pharmacology
  • Acinar Cells / drug effects
  • Acinar Cells / metabolism
  • Animals
  • Autoantibodies / immunology
  • Calcium Signaling / drug effects
  • Dry Eye Syndromes / metabolism
  • Dry Eye Syndromes / pathology*
  • Dry Eye Syndromes / veterinary
  • Epinephrine / pharmacology
  • Epithelium, Corneal / metabolism
  • Immunoglobulins / blood
  • Inflammation
  • Inositol 1,4,5-Trisphosphate Receptors / deficiency
  • Inositol 1,4,5-Trisphosphate Receptors / genetics
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Lacrimal Apparatus / metabolism
  • Lacrimal Apparatus / pathology
  • Mice
  • Mice, Knockout
  • Ribonucleoproteins / immunology
  • Tears / metabolism


  • Autoantibodies
  • Immunoglobulins
  • Inositol 1,4,5-Trisphosphate Receptors
  • Ribonucleoproteins
  • SS-A antigen
  • Acetylcholine
  • Epinephrine

Grant support

This work was supported by a Grant-in-Aid for Challenging Exploratory Research (No. 20659272) from The Japanese Ministry of Education, Culture, Sports, Science and Technology, the Nagao Memorial Fund, the Moritani Scholarship Foundation (C.H.), JSPS KAKENHI Grant Number 20220007 (K.M.), and the Japan Science and Technology Agency (K.M.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.