Cftr and ENaC ion channels mediate NaCl absorption in the mouse submandibular gland

Abstract

Cystic fibrosis is caused by mutations in CFTR, the cystic fibrosis transmembrane conductance regulator gene. Disruption of CFTR-mediated anion conductance results in defective fluid and electrolyte movement in the epithelial cells of organs such as the pancreas, airways and sweat glands, but the function of CFTR in salivary glands is unclear. Salivary gland acinar cells produce an isotonic, plasma-like fluid, which is subsequently modified by the ducts to produce a hypotonic, NaCl-depleted final saliva. In the present study we investigated whether submandibular salivary glands (SMGs) in F508 mice (Cftr F/ F ) display ion transport defects characteristic of cystic fibrosis in other tissues. Immunolocalization and whole-cell recordings demonstrated that Cftr and the epithelial Na + (ENaC) channels are co-expressed in the apical membrane of submandibular duct cells, consistent with the significantly higher saliva [NaCl] observed in vivo in Cftr F/ F mice. In contrast, Cftr and ENaC channels were not detected in acinar cells, nor was saliva production affected in Cftr F/ F mice, implying that Cftr contributes little to the fluid secretion process in the mouse SMG. To identify the source of the NaCl absorption defect in Cftr F/ F mice, saliva was collected from ex vivo perfused SMGs. Cftr F/ F glands secreted saliva with significantly increased [NaCl]. Moreover, pharmacological inhibition of either Cftr or ENaC in the ex vivo SMGs mimicked the Cftr F/ F phenotype. In summary, our results demonstrate that NaCl absorption requires and is likely to be mediated by functionally dependent Cftr and ENaC channels localized to the apical membranes of mouse salivary gland duct cells.

A fluid secretion pathway unmasked by acinar-specific Tmem16A gene ablation in the adult mouse salivary gland

“…However, mouse SMG duct cells express cAMPdependent Cftr Cl − channels that are regulated by β-adrenergic receptor activation (8). Consequently, we asked whether IPRinduced fluid secretion might occur in the duct epithelium through a Cftr channel-dependent mechanism.…”

“…Our results demonstrate that muscarinic Ca 2+ -dependent fluid secretion is abolished in the salivary glands of Tmem16A null (Tmem16A −/− ) mice, whereas β-adrenergic receptor-stimulated cAMP-dependent fluid secretion is normal. Given that cAMP-dependent Cftr Cl − channels are gated on β-adrenergic receptor stimulation and are highly expressed in salivary glands (8), we also analyzed fluid secretion in mice carrying the homologous ΔF508 mutation of the human CFTR channel, the mutation most frequently observed in cystic fibrosis patients (9). Saliva secretion induced by β-adrenergic receptor agonist isoproterenol (IPR) was unaffected in mice lacking Cftr and ClC-2 Cl − channels (Cftr ΔF508/ΔF508 and Clcn2 −/− mice, respectively).…”

Oral cavity health among cystic fibrosis patients: Literature overview

“…Therefore, it indirectly regulates the flow of carbonate, sodium and potassium ions. [5][6][7] So far, over 1600 mutations of the CFTR gene have been reported. They all result in impairment of the structure and functioning of the chloride channel, which in turn leads to disturbance of the general ion balance of the epithelium.…”

Transepithelial Bicarbonate Secretion: Lessons from the Pancreas

“…þ -and fluid-absorbing epithelial cells express NHE in the apical membrane, which mediates electroneutral Na þ uptake (Cook et al 2002;Catalan et al 2010). NHE2 and NHE3 are the major NHE isotypes expressed in the apical membrane of epithelial cells.…”

“…Some surface epithelial cells of respiratory and digestive tracts and duct cells of salivary glands express ENaC at the apical membrane, which mediates electrogenic Na þ uptake in these cells (Cook et al 2002;Catalan et al 2010). However, pancreatic duct cells do not express ENaC, because they do not absorb Na þ .…”