Loss of STIM1 and STIM2 in Salivary Glands Disrupts ANO1 Function but Does Not Induce Sjogren's Disease

Function (Oxf). 2025 Feb 12;6(1):zqae047. doi: 10.1093/function/zqae047.

Abstract

Ca2+ signaling via the store-operated Ca2+ entry (SOCE) mediated by STIM1 and STIM2 proteins and the ORAI1 Ca2+ channel is important in saliva fluid secretion and has been associated with Sjogren's disease (SjD). However, there are no studies addressing STIM1/2 dysfunction in salivary glands or SjD in animal models. We report that mice lacking Stim1 and Stim2 [Stim1/2K14Cre(+)] in salivary glands exhibited reduced Ca2+ levels and hyposalivate. SOCE was functionally required for the activation of the Ca2+ activated Cl- channel ANO1. Ageing Stim1/2K14Cre(+) mice showed no evidence of lymphocytic infiltration or increased levels of autoantibodies characteristic of SjD, possibly associated with a downregulation of toll-like receptor 8 (Tlr8) expression. Salivary gland biopsies of SjD patients showed increased expression of STIM1 and TLR7/8. Our study shows that SOCE activates ANO1 function and fluid secretion in salivary glands and highlights a potential link between SOCE and TLR signaling in SjD.

Keywords: ANO1; STIM1; Sjogren’s disease; calcium signaling; hyposalivation; tool-like receptors.

MeSH terms

  • Animals
  • Anoctamin-1
  • Calcium / metabolism
  • Calcium Signaling
  • Female
  • Humans
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins* / genetics
  • Neoplasm Proteins* / metabolism
  • Saliva / metabolism
  • Salivary Glands* / metabolism
  • Salivary Glands* / pathology
  • Sjogren's Syndrome* / genetics
  • Sjogren's Syndrome* / metabolism
  • Sjogren's Syndrome* / pathology
  • Stromal Interaction Molecule 1* / genetics
  • Stromal Interaction Molecule 1* / metabolism
  • Stromal Interaction Molecule 2* / genetics
  • Stromal Interaction Molecule 2* / metabolism

Substances

  • Stromal Interaction Molecule 1
  • Stromal Interaction Molecule 2
  • Stim1 protein, mouse
  • Stim2 protein, mouse
  • Anoctamin-1
  • ANO1 protein, mouse
  • Neoplasm Proteins
  • Calcium
  • ANO1 protein, human
  • STIM1 protein, human