Loss of STIM1 and STIM2 in salivary glands disrupts ANO1 function but does not induce Sjogren's disease.

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.

A mathematical model of ENaC and Slc26a6 regulation by CFTR in salivary gland ducts.

Cystic fibrosis (CF) is a genetic disease caused by the mutations of cystic fibrosis transmembrane conductance regulator (), the cystic fibrosis transmembrane conductance regulator gene. Cftr is a critical ion channel expressed in the apical membrane of mouse salivary gland striated duct cells. Although Cftr is primarily a Cl channel, its knockout leads to higher salivary Cl and Na concentrations and lower pH.

Loss of STIM1 and STIM2 in salivary glands disrupts ANO1 function but does not induce Sjogren's disease.

Sjogren's disease (SjD) is an autoimmune disease characterized by xerostomia (dry mouth), lymphocytic infiltration into salivary glands and the presence of SSA and SSB autoantibodies. Xerostomia is caused by hypofunction of the salivary glands and has been involved in the development of SjD. Saliva production is regulated by parasympathetic input into the glands initiating intracellular Ca signals that activate the store operated Ca entry (SOCE) pathway eliciting sustained Ca influx.

Structural and functional analysis of salivary intercalated duct cells reveals a secretory phenotype.

Currently, all salivary ducts (intercalated, striated and collecting) are assumed to function broadly in a similar manner, reclaiming ions that were secreted by the secretory acinar cells while preserving fluid volume and delivering saliva to the oral cavity. Nevertheless, there has been minimal investigation into the structural and functional differences between distinct types of salivary duct cells. Therefore, in this study, the expression profile of proteins involved in stimulus-secretion coupling, as well as the function of the intercalated duct (ID) and striated duct cells, was examined.

Missense mutations in inositol 1,4,5-trisphosphate receptor type 3 result in leaky Ca channels and activation of store-operated Ca entry.

Mutations in all subtypes of the inositol 1,4,5-trisphosphate receptor Ca release channel are associated with human diseases. In this report, we investigated the functionality of three neuropathy-associated missense mutations in IPR3 (V615M, T1424M, and R2524C). The mutants only exhibited function when highly over-expressed compared to endogenous hIPR3.

Simulation of Calcium Dynamics in Realistic Three-Dimensional Domains.

The cytosolic concentration of free calcium ions ([Ca2+]) is an important intracellular messenger in most cell types, and the spatial distribution of [Ca2+] is often critical. In a salivary gland acinar cell, a polarised epithelial cell, whose principal function is to transport water and thus secrete saliva, [Ca2+] controls the secretion of primary saliva, but increases in [Ca2+] are localised to the apical regions of the cell. Hence, any quantitative explanation of how [Ca2+] controls saliva secretion must take into careful account the spatial distribution of the various Ca2+ sources, Ca2+ sinks, and Ca2+-sensitive ion channels.

A Mathematical Model of Salivary Gland Duct Cells.

Saliva is produced in two stages in the salivary glands: the secretion of primary saliva by the acinus and the modification of saliva composition to final saliva by the intercalated and striated ducts. In order to understand the saliva modification process, we develop a mathematical model for the salivary gland duct. The model utilises the realistic 3D structure of the duct reconstructed from an image stack of gland tissue.

Highly localized intracellular Ca signals promote optimal salivary gland fluid secretion.

Salivary fluid secretion involves an intricate choreography of membrane transporters to result in the trans-epithelial movement of NaCl and water into the acinus lumen. Current models are largely based on experimental observations in enzymatically isolated cells where the Ca signal invariably propagates globally and thus appears ideally suited to activate spatially separated Cl and K channels, present on the apical and basolateral plasma membrane, respectively. We monitored Ca signals and salivary secretion in live mice expressing GCamp6F, following stimulation of the nerves innervating the submandibular gland.

Disease-associated mutations in inositol 1,4,5-trisphosphate receptor subunits impair channel function.

The inositol 1,4,5-trisphosphate (IP) receptors (IPRs), which form tetrameric channels, play pivotal roles in regulating the spatiotemporal patterns of intracellular calcium signals. Mutations in IPRs have been increasingly associated with many debilitating human diseases such as ataxia, Gillespie syndrome, and generalized anhidrosis. However, how these mutations affect IPR function, and how the perturbation of as-sociated calcium signals contribute to the pathogenesis and severity of these diseases remains largely uncharacterized.

An inside job: Annexin 1A-Inositol 1,4,5-trisphosphate receptor interaction conveys endoplasmic reticulum luminal Ca sensitivity.

Cytoplasmic Ca is a pivotal regulator of IPR activity. It is however controversial whether the [Ca] in the Endoplasmic Reticulum lumen also directly regulates channel function. We highlight a recent paper that demonstrates that luminal [Ca] potently inhibits IPR activity.