Mucociliary clearance, the continuous removal of mucus-trapped particles by cilia-driven directed transport of the airway lining fluid, is the primary innate defense mechanism of the airways. It is potently activated by acetylcholine (ACh) addressing muscarinic receptors with a currently less defined role of nicotinic ACh receptors (nAChR). We here set out to determine their contribution in driving ciliary activity in an explanted mouse trachea preparation utilizing selected agonists and antagonists and nAChR-subunit deficient mice. Nicotine (100 microM) induced an increase in ciliary beat frequency, accompanied by a sharp, but not long lasting increase in particle transport speed (PTS) on the mucosal surface showing marked desensitization within the next 30 min. Nicotine-induced PTS acceleration was sensitive to the general nAChR inhibitors mecamylamine and d-tubocurarine as well as to the alpha3beta4-nAChR antagonist alpha-conotoxin AulB, but not to other antagonists primarily addressing alpha3beta2-nAChR or alpha4-, alpha7- and alpha9-containing nAChR. Agonists at alpha3beta*-nAChR (epibatidine, cytisine), but not cotinine mimicked the effect. Tracheas from mice with genetic deletion of nAChR subunits alpha5, alpha7, alpha9, alpha10, alpha9/10, and beta2 retained full PTS response to nicotine, whereas this was entirely lost in tracheas from mice lacking the beta4-subunit. Collectively, our data show that nicotinic stimulation of alpha3beta4-nAChR acutely increases PTS to the same extent as the established strong activator ATP. In view of the marked desensitization observed in the present setting, the physiological relevance of these receptors in adapting mucociliary clearance to rapidly changing endogenous or environmental stimuli remains open.
- Perniss, A.
- Latz, A.
- Boseva, I.
- Papadakis, T.
- Dames, C.
- Meisel, C.
- Meisel, A.
- Scholze, P.
- Kummer, W.
- Krasteva-Christ, G.
Keywords
- Mucociliary clearance
- Nicotine
- Non-neuronal acetylcholine
- nAChR
