Son Ga-Yeon, Zou Anna, Wahl Amanda, Huang Kai Ting, Zorgit Saruul, Vinu Manikandan, Zhou Fang, Wagner Larry, Idaghdour Youssef, Yule David I, Feske Stefan, Lacruz Rodrigo S
Department of Molecular Pathobiology, New York University College of Dentistry, New York 10010, USA.
Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642, USA.
Function (Oxf). 2025 Feb 12;6(1). doi: 10.1093/function/zqae047.
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.
由STIM1和STIM2蛋白以及ORAI1钙通道介导的通过储存操纵性钙内流（SOCE）的钙离子信号传导在唾液分泌中很重要，并且与干燥综合征（SjD）有关。然而，尚无关于动物模型中唾液腺或干燥综合征中STIM1/2功能障碍的研究。我们报告称，唾液腺中缺乏Stim1和Stim2 [Stim1/2K14Cre(+)] 的小鼠表现出钙离子水平降低和唾液分泌减少。SOCE在功能上是激活钙离子激活的氯离子通道ANO1所必需的。衰老的Stim1/2K14Cre(+) 小鼠没有显示出淋巴细胞浸润的证据或干燥综合征特征性自身抗体水平升高，这可能与Toll样受体8（Tlr8）表达下调有关。干燥综合征患者的唾液腺活检显示STIM1和TLR7/8表达增加。我们的研究表明，SOCE激活唾液腺中的ANO1功能和液体分泌，并突出了干燥综合征中SOCE与TLR信号传导之间的潜在联系。
