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K2P2.1 channels modulate the pH- and mechanosensitivity of pancreatic stellate cells

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Title: K2P2.1 channels modulate the pH- and mechanosensitivity of pancreatic stellate cells
Authors: Micol Rugi, Verena Hofschröer, Zoltán Pethő, Benjamin Soret, Thorsten Loeck, Albrecht Schwab
Source: Pflugers Arch
Publisher Information: Springer Science and Business Media LLC, 2024.
Publication Year: 2024
Subject Terms: Mice, Inbred C57BL, Mice, Potassium Channels, Tandem Pore Domain, Cell Movement, Mechanotransduction, Cellular [MeSH], Mechanosensitivity, Mice, Inbred C57BL [MeSH], Cell Movement/physiology [MeSH], Ion Channels, Receptors and Transporters, Membrane Potentials/physiology [MeSH], Potassium Channels, Tandem Pore Domain/genetics [MeSH], Animals [MeSH], PH, Pancreatic Stellate Cells, Pancreatic Stellate Cells/metabolism [MeSH], K, Mice [MeSH], Potassium Channels, Tandem Pore Domain/metabolism [MeSH], Carcinoma, Pancreatic Ductal/pathology [MeSH], Hydrogen-Ion Concentration [MeSH], Carcinoma, Pancreatic Ductal/metabolism [MeSH], Animals, Hydrogen-Ion Concentration, Mechanotransduction, Cellular, Membrane Potentials, Carcinoma, Pancreatic Ductal
Description: Pancreatic stellate cells (PSCs) are central in the development of acute pancreatitis and tumor fibrosis in pancreatic ductal adenocarcinoma (PDAC). Fibrosis and a unique pH landscape represent characteristic properties of the PDAC microenvironment. Mechanosensitive ion channels are involved in the activation of PSCs. Among these channels, K2P2.1 has not yet been studied in PSCs. K2P2.1 channels are pH- and mechanosensitive. We confirmed K2P2.1 expression in PSCs by RT-qPCR and immunofluorescence. PSCs from K2P2.1+/+ and K2P2.1−/− mice were studied under conditions mimicking properties of the PDAC microenvironment (acidic extracellular pH (pHe), ambient pressure elevated by + 100 mmHg). Migration and the cell area were taken as surrogates for PSC activation and evaluated with live cell imaging. pHe-dependent changes of the membrane potential of PSCs were investigated with DiBAC4(3), a voltage-sensitive fluorescent dye. We observed a correlation between morphological activation and progressive hyperpolarization of the cells in response to changes in pHe and pressure. The effect was in part dependent on the expression of K2P2.1 channels because the membrane potential of K2P2.1+/+ PSCs was always more hyperpolarized than that of K2P2.1−/− PSCs. Cell migration velocity of K2P2.1+/+ cells decreased upon pressure application when cells were kept in an acidic medium (pHe 6.6). This was not the case in K2P2.1−/− PSCs. Taken together, our study highlights the critical role of K2P2.1 channels in the combined sensing of environmental pressure and pHe by PSCs and in coordinating cellular morphology with membrane potential dynamics. Thus, K2P2.1 channels are important mechano-sensors in murine PSCs.
Document Type: Article
Other literature type
Language: English
ISSN: 1432-2013
0031-6768
DOI: 10.1007/s00424-024-03021-z
Access URL: https://pubmed.ncbi.nlm.nih.gov/39325089
https://repository.publisso.de/resource/frl:6522707
Rights: CC BY
Accession Number: edsair.doi.dedup.....2c52fa82b514028ff20c337fca500baf
Database: OpenAIRE
Description
Abstract:Pancreatic stellate cells (PSCs) are central in the development of acute pancreatitis and tumor fibrosis in pancreatic ductal adenocarcinoma (PDAC). Fibrosis and a unique pH landscape represent characteristic properties of the PDAC microenvironment. Mechanosensitive ion channels are involved in the activation of PSCs. Among these channels, K2P2.1 has not yet been studied in PSCs. K2P2.1 channels are pH- and mechanosensitive. We confirmed K2P2.1 expression in PSCs by RT-qPCR and immunofluorescence. PSCs from K2P2.1+/+ and K2P2.1−/− mice were studied under conditions mimicking properties of the PDAC microenvironment (acidic extracellular pH (pHe), ambient pressure elevated by + 100 mmHg). Migration and the cell area were taken as surrogates for PSC activation and evaluated with live cell imaging. pHe-dependent changes of the membrane potential of PSCs were investigated with DiBAC4(3), a voltage-sensitive fluorescent dye. We observed a correlation between morphological activation and progressive hyperpolarization of the cells in response to changes in pHe and pressure. The effect was in part dependent on the expression of K2P2.1 channels because the membrane potential of K2P2.1+/+ PSCs was always more hyperpolarized than that of K2P2.1−/− PSCs. Cell migration velocity of K2P2.1+/+ cells decreased upon pressure application when cells were kept in an acidic medium (pHe 6.6). This was not the case in K2P2.1−/− PSCs. Taken together, our study highlights the critical role of K2P2.1 channels in the combined sensing of environmental pressure and pHe by PSCs and in coordinating cellular morphology with membrane potential dynamics. Thus, K2P2.1 channels are important mechano-sensors in murine PSCs.
ISSN:14322013
00316768
DOI:10.1007/s00424-024-03021-z