Involvement of the TREK‐1 channel in human alveolar cell membrane potential and its regulation by inhibitors of the chloride current

Abstract

K+ channels of the alveolar epithelium control the driving force acting on the ionic and solvent flow through the cell membrane contributing to the maintenance of cell volume and the constitution of epithelial lining fluid. In the present work, we analyze the effect of the Cl− channel inhibitors: (4‐[(2‐butyl‐6,7‐dichloro‐2‐cyclopentyl‐2,3‐dihydro‐1‐oxo‐inden‐5‐yl)oxy] butanoic acid (DCPIB) and 9‐anthracenecarboxylic acid (9‐AC) on the total current in a type II pneumocytes (A549 cell line) model by patch clamp, immunocytochemical, and gene knockdown techniques. We noted that DCPIB and 9‐AC promote the activation of K conductance. In fact, they significantly increase the intensity of the current and shift its reversal potential to values more negative than the control. By silencing outward rectifier channel in its anoctamin 6 portion, we excluded a direct involvement of Cl− ions in modulation of IK and, by means of functional tests with its specific inhibitor spadin, we identified the TREK‐1 channel as the presumable target of both drugs. As the activity of TREK‐1 has a key role for the correct functioning of the alveolar epithelium, the identification of DCPIB and 9‐AC molecules as its activators suggests their possible use to build new pharmacological tools for the modulation of this channel.

Proteomic and ultrastructural analysis of Clara cell and type II alveolar epithelial cell-type lung cancer cells

“…Clara cell and type II alveolar epithelial cell-type lung adenocarcinoma cells differ in terms of morphology under electron microscopy, but it still remains unclear how their cell lines; and both cell types with Clara cell granules predominating in the NCI-H441-4 and NCI-H1334 cell lines (9). The differentiation characteristics of Clara cell type and type II alveolar epithelial cell type also have been observed in NCI-H358 and A549 cells, respectively (6)(7)(8)(9)(10)(11). Under electron microscopy, we confirmed that all six cell lines conformed to the characteristics of lung adenocarcinoma.…”

“…Thus, it is still questionable whether CC10 is suitable as a biomarker for Clara cell-type lung adenocarcinoma cells. SP-A, SP-B, and SP-D are synthesized by type II alveolar epithelial cells and Clara cells, while SP-C is produced only by type II alveolar epithelial cells in normal lungs ( 10 , 33 , 34 ). To the best of our knowledge, SP-C as a theoretical biomarker for the identification of type II alveolar epithelial cancer cells has not been verified yet.…”

K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury

“…Limited information form human ex vivo studies point towards Em values between − 15 and − 20 mV in bronchial epithelial cells 91,93 . Notably, other studies estimate the resting Em in AT2 cells as low as 0 to − 5 mV 94,95 . Despite these ranges in Em for lung resident cells, it is important to realize that the Em of epithelial and endothelial cells is much lower than the Em of excitable cells such as neurons and cardiomyocytes, in which the Em ranges between − 60 and − 90 mV 96,97 .…”

Small molecule SWELL1-LRRC8 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes

“…Moreover, SN-401 mediated rescue of islet insulin secretion under gluco-lipotoxic conditions in vitro also requires SWELL1. Finally, it is important to note that the studies demonstrating promiscuity of SN-401/DCPIB with other ion channel targets all applied DCPIB at ~10-200 µM [65][66][67][68][69][70] . This is 100-200-fold higher than the concentrations required to potentiate SWELL1-dependent signaling in vitro ( Fig.…”