A new role for an old drug: Ambroxol triggers lysosomal exocytosis via pH-dependent Ca2+ release from acidic Ca2+ stores

Fois, G, Hobi, N, Felder, E, Ziegler, A, Miklavc, P ORCID: https://orcid.org/0000-0002-9419-4293, Walther, P, Radermacher, P, Haller, T and Dietl, P 2015, 'A new role for an old drug: Ambroxol triggers lysosomal exocytosis via pH-dependent Ca2+ release from acidic Ca2+ stores' , Cell Calcium, 58 (6) , pp. 628-637.

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Abstract

Ambroxol (Ax) is a frequently prescribed drug used to facilitate mucociliary clearance, but its mode of action is yet poorly understood. Here we show by X-ray spectroscopy that Ax accumulates in lamellar bodies (LBs), the surfactant storing, secretory lysosomes of type II pneumocytes. Using lyso- and acidotropic substances in combination with fluorescence imaging we confirm that these vesicles belong to the class of acidic Ca2+ stores. Ax lead to a significant neutralization of LB pH, followed by intracellular Ca2+ release, and to a dose-dependent surfactant exocytosis. Ax-induced Ca2+ release was significantly reduced and slowed down by pretreatment of the cells with bafilomycin A1 (Baf A1), an inhibitor of the vesicular H+ ATPase. These results could be nearly reproduced with NH3/NH4+. The findings suggest that Ax accumulates within LBs and severely affects their H+ and Ca2+ homeostasis. This is further supported by an Ax-induced change of nanostructural assembly of surfactant layers. We conclude that Ax profoundly affects LBs presumably by disordering lipid bilayers and by acting as a weak base. The pH change triggers – at least in part – Ca2+ release from stores and secretion of surfactant from type II cells. This novel mechanism of Ax as a lysosomal secretagogue may also play a role for its recently discussed use for lysosomal storage and other degenerative diseases.

Item Type:	Article
Schools:	Schools > School of Environment and Life Sciences
Journal or Publication Title:	Cell Calcium
Publisher:	Elsevier
ISSN:	0143-4160
Funders:	Deutsche Forschungsgemeinschaft, DFG grant DI 1402 (to P.D.), Margarete von Wrangell scholarship from the Ministry of Science, Research and the Arts Baden-Württemberg (to P.M.), Carl Zeiss foundation, Germany (to N.H.)
Depositing User:	P Miklavc
Date Deposited:	04 Oct 2016 08:45
Last Modified:	07 Nov 2019 15:09
URI:	http://usir.salford.ac.uk/id/eprint/40251

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