title: Mice lacking inositol 1,4,5-trisphosphate receptors exhibit dry eye.
abstract: 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.
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Shinjuku, Tokyo, Japan; Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Inaba
authors.affiliation: Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Hisatsune
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Ebisui
authors.affiliation: Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako, Saitama, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Ogawa
authors.affiliation: Department of Pharmacy, Chiba Institute of Science, Choshi, Chiba, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Matsui
authors.affiliation: Department of Rheumatology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takeuchi
authors.affiliation: Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako, Saitama, Japan; Calcium Oscillation Project, International Cooperative Research Project-Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsubota
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D020013:Calcium Signaling / Q000187:drug effects; D015352:Dry Eye Syndromes / Q000378:metabolism / Q000473:pathology* / Q000662:veterinary; D004837:Epinephrine / Q000494:pharmacology; D019573:Epithelium, Corneal / Q000378:metabolism; D007136:Immunoglobulins / Q000097:blood; D007249:Inflammation; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007765:Lacrimal Apparatus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D012261:Ribonucleoproteins / Q000276:immunology; D013666:Tears / Q000378:metabolism; D000099207:SS-A Antigen
chemical_list: D000109:Acetylcholine; D001323:Autoantibodies; D004837:Epinephrine; D007136:Immunoglobulins; D053496:Inositol 1,4,5-Trisphosphate Receptors; D012261:Ribonucleoproteins; D000099207:SS-A Antigen