Muscarinic receptor subtypes in cilia-driven transport and airway epithelial development

¹ Institut für Anatomie und Zellbiologie and University of Giessen Lung Center, Justus-Liebig-Universität Giessen, Giessen, Germany
² Institut für Anatomie und Zellbiologie and University of Giessen Lung Center, Justus-Liebig-Universität Giessen, Giessen, Germany; and Dept of Anatomy and Histology, Flinders University, Adelaide, SA, Australia
³ Institut für Anatomie und Zellbiologie and University of Giessen Lung Center, Justus-Liebig-Universität Giessen, Giessen, Germany; and Abteilung für Anaesthesie, Operative Intensivmedizin, Schmerztherapie, Justus-Liebig-Universität Giessen, Giessen, Germany
⁴ Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
⁵ Institut für Anatomie und Zellbiologie and University of Giessen Lung Center, Justus-Liebig-Universität Giessen, Giessen, Germany; and Institut für Anatomie, Zentrum für Medizinische Struktur- und Zellbiologie, Universität zu Lübeck, Lübeck, Germany

^* To whom correspondence should be addressed. E-mail: koenig{at}anat.uni-luebeck.de.

	Abstract

Ciliary beating of airway epithelial cells drives the removal of mucus and particles from the airways. Mucociliary transport and possibly airway epithelial development are governed by muscarinic acetylcholine receptors but the precise roles of the subtypes involved are unknown.

This issue was addressed by determining cilia-driven particle transport, ciliary beat frequency, and the composition and ultrastructural morphology of the tracheal epithelium in M1–M5 muscarinic receptor gene-deficient mice.

Knockout of M3 muscarinic receptors prevented an increase in particle transport speed and ciliary beat frequency in response to muscarine. Furthermore, the ATP response after application of muscarine was blunted. Pretreatment with atropine before application of muscarine restored the response to ATP. Additional knockout of the M2 receptor in these mice partially restored the muscarine effect most likely through the M1 receptor and normalized the ATP response. M1, M4, and M5 receptor deficient mice exhibited normal responses to muscarine. None of the investigated mutant mouse strains had any impairment of epithelial cellular structure or composition.

In conclusion, M3 receptors stimulate whereas M2 receptors inhibit cilia-driven particle transport. The M1 receptor increases cilia-driven particle transport if the M3 and M2 receptor are missing. None of the receptors is necessary for epithelial development.