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Media type:
E-Article
Title:
Luminal cholinergic signalling in airway lining fluid: a novel mechanism for activating chloride secretion via Ca2+‐dependent Cl‐ and K+ channels
Contributor:
Hollenhorst, Monika I;
Lips, Katrin S;
Wolff, Miriam;
Wess, Jürgen;
Gerbig, Stefanie;
Takats, Zoltan;
Kummer, Wolfgang;
Fronius, Martin
Description:
<jats:p><jats:bold>BACKGROUND AND PURPOSE</jats:bold> Recent studies detected the expression of proteins involved in cholinergic metabolism in airway epithelial cells, although the function of this non‐neuronal cholinergic system is not known in detail. Thus, this study focused on the effect of luminal ACh as a regulator of transepithelial ion transport in epithelial cells.</jats:p><jats:p><jats:bold>EXPERIMENTAL APPROACH</jats:bold> RT‐PCR experiments were performed using mouse tracheal epithelial cells for ChAT and organic cation transporter (OCT) transcripts. Components of tracheal airway lining fluid were analysed with desorption electrospray ionization (DESI) MS. Effects of nicotine on mouse tracheal epithelial ion transport were examined with Ussing‐chamber experiments.</jats:p><jats:p><jats:bold>KEY RESULTS</jats:bold> Transcripts encoding ChAT and OCT1–3 were detected in mouse tracheal epithelial cells. The DESI experiments identified ACh in the airway lining fluid. Luminal ACh induced an immediate, dose‐dependent increase in the transepithelial ion current (EC<jats:sub>50</jats:sub>: 23.3 µM), characterized by a transient peak and sustained plateau current. This response was not affected by the Na<jats:sup>+</jats:sup>‐channel inhibitor amiloride. The Cl<jats:sup>‐</jats:sup>‐channel inhibitor niflumic acid or the K<jats:sup>+</jats:sup>‐channel blocker Ba<jats:sup>2+</jats:sup> attenuated the ACh effect. The calcium ionophore A23187 mimicked the ACh effect. Luminal nicotine or muscarine increased the ion current. Experiments with receptor gene‐deficient animals revealed the participation of muscarinic receptor subtypes M<jats:sub>1</jats:sub> and M<jats:sub>3</jats:sub>.</jats:p><jats:p><jats:bold>CONCLUSIONS AND IMPLICATIONS</jats:bold> The presence of luminal ACh and activation of transepithelial ion currents by luminal ACh receptors identifies a novel non‐neuronal cholinergic pathway in the airway lining fluid. This pathway could represent a novel drug target in the airways.</jats:p>