Avertin®, but Not Volatile Anesthetics Addressing the Two-Pore Domain K+ Channel, TASK-1, Slows Down Cilia-Driven Particle Transport in the Mouse Trachea.

Ghulam Murtaza,Wolfgang Kummer,Petra Mermer,Uwe Pfeil,Anirban Bhunia

doi:10.1371/journal.pone.0167919

Ghulam Murtaza, Wolfgang Kummer + Show 3 more

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https://doi.org/10.1371/journal.pone.0167919

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Abstract

RationaleVolatile anesthetics inhibit mucociliary clearance in the airways. The two-pore domain K+ channel, TASK-1, represents one of their molecular targets in that they increase its open probability. Here, we determine whether particle transport speed (PTS) at the mucosal surface of the mouse trachea, an important factor of the cilia-driven mechanism in mucociliary clearance, is regulated by TASK-1.Methodology/ResultsRT-PCR analysis revealed expression of TASK-1 mRNA in the manually dissected and laser-assisted microdissected tracheal epithelium of the mouse. Effects of anesthetics (isoflurane and Avertin®) and TASK-1 inhibitors (anandamide and A293) on ciliary activity were investigated by assessment of PTS at the mucosal surface of the explanted and opened murine trachea. Neither TASK-1 inhibitors nor isoflurane had any impact on basal and ATP-stimulated PTS. Avertin® reduced basal PTS, and ATP-stimulated PTS decreased in its presence in wild-type (WT) mice. Avertin®-induced decrease in basal PTS persisted in WT mice in the presence of TASK-1 inhibitors, and in two different strains of TASK-1 knockout mice.Conclusions/SignificanceOur findings indicate that TASK-1 is expressed by the tracheal epithelium but is not critically involved in the regulation of tracheal PTS in mice. Avertin® reduces PTS independent of TASK-1.

Highlights

Mucociliary clearance (MCC) is the defence mechanism by which airways get rid of inhaled pathogens and particles from environment and clean themselves [1, 2]
As our study was based on the presence of TASK-1 in the airways and its role in MCC, we performed PCR to evaluate the expression of TASK-1 mRNA in the tracheal epithelium
The major finding of this study is that, despite TASK-1 is expressed in the murine tracheal epithelium, neither inhibitors nor an activator of TASK-1 modulate cilia-driven particle transport at the mucosal surface

Summary

Introduction

Mucociliary clearance (MCC) is the defence mechanism by which airways get rid of inhaled pathogens and particles from environment and clean themselves [1, 2]. In carotid body glomus cells, it has directly been shown that this causes a rise in intracellular calcium concentration ([Ca2+]i) due to increased entry through voltage-gated Ca2+ channels [11], and this is proposed as the underlying mechanism causing pulmonary artery smooth muscle cells constriction in response to the TASK inhibitor anandamide [12]. In ciliated cells of the respiratory epithelium, an increase in [Ca2+]i causes a rapid increase in ciliary beat frequency (CBF) and lowering [Ca2+]i is associated with a decrease in CBF [13, 14]. Activation of these channels by anesthetics may lead to decrease in [Ca2+]i and ciliary activity and resulting in reduced MCC. Anesthetics would even have a stimulatory effect on CBF if acting through TASK channels

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