Luminal cholinergic signalling in airway lining fluid: a novel mechanism for activating chloride secretion via Ca²⁺‐dependent Cl^‐ and K⁺ channels

Abstract

BACKGROUND AND PURPOSERecent 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. EXPERIMENTAL APPROACHRT-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. KEY RESULTSTranscripts 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 (EC50: 23.3 mM), characterized by a transient peak and sustained plateau current. This response was not affected by the Na CONCLUSIONS AND IMPLICATIONSThe 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.

Tracheal brush cells release acetylcholine in response to bitter tastants for paracrine and autocrine signaling

“…4 However, M1R-mRNA was not detected in Type II taste cells and no negative cholinergic feedback loop was found. Consistent with previous reports, 15,16,46 we have observed that MC is regulated by ACh and that this ACh-induced increase in cilia-driven PTS is M3Rdependent. 38 Thus, this negative regulation seems to be specific for the nontaste organs but the involved MR are organ-specific.…”

“…[4][5][6][7][8] Based on the recent advances in single-cell RNA-sequencing it became evident that more than one BC type exists in the airways and BC signature varies in different organs. [14][15][16][17] In the human upper airways nitric oxide released in response to taste receptor (TasR) stimulation increases ciliary beat, [18][19][20][21] but there is no proof that the same mechanism operates in the lower airways or additional mechanisms are influencing MC. 7,12 Yet, it remains elusive if these cells indeed synthesize and release ACh.…”

Identification of cholinergic chemosensory cells in mouse tracheal and laryngeal glandular ducts

“…In fact, ACh stimulates the ciliary beat frequency and particle transport speed at the tracheal surface via the M3 subtype of muscarinic receptors in the murine trachea [49]. It is also likely that ACh released into the lumen contributes to the activation of transepithelial ion currents and fluid secretion by luminal ACh receptors as was shown recently for tracheal epithelial cells [50,51]. Consistent with this, bitter substances were found to increase the anion transport and fluid secretion in the rat colon [52].…”

Choline transporter‐like protein 4 (CTL4) links to non‐neuronal acetylcholine synthesis

“…; Hollenhorst et al . ). In both lung cancer and colon cancer, ACh acts as an autocrine growth factor for cancer growth and development (Song et al .…”