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Functional expression of the proton sensors ASIC1a, TMEM206, and OGR1 together with BKCa channels is associated with cell volume changes and cell death under strongly acidic conditions in DAOY medulloblastoma cells

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Title: Functional expression of the proton sensors ASIC1a, TMEM206, and OGR1 together with BKCa channels is associated with cell volume changes and cell death under strongly acidic conditions in DAOY medulloblastoma cells
Authors: Karolos-Philippos Pissas, Stefan Gründer, Yuemin Tian
Source: Pflugers Arch
Pflügers Archiv 476(6), 923-937 (2024). doi:10.1007/s00424-024-02964-7
Publisher Information: Springer Science and Business Media LLC, 2024.
Publication Year: 2024
Subject Terms: 0301 basic medicine, 0303 health sciences, Cell Death, Ion channels, Receptors and Transporters, Hydrogen-Ion Concentration, Receptors, G-Protein-Coupled, Acid Sensing Ion Channels, 03 medical and health sciences, Chloride Channels, Cell Line, Tumor, Humans, Calcium, Receptors, G-Protein-Coupled/metabolism [MeSH], Cell Line, Tumor [MeSH], Medulloblastoma, Cerebellar Neoplasms/pathology [MeSH], Medulloblastoma/pathology [MeSH], Cell Size [MeSH], Chloride Channels/metabolism [MeSH], Medulloblastoma/metabolism [MeSH], Cell Death [MeSH], Receptors, G-Protein-Coupled/genetics [MeSH], Acid Sensing Ion Channels/genetics [MeSH], Calcium/metabolism [MeSH], Cell volume regulation, Humans [MeSH], Cell death, Cerebellar Neoplasms/metabolism [MeSH], Chloride Channels/genetics [MeSH], Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/genetics [MeSH], Hydrogen-Ion Concentration [MeSH], Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/metabolism [MeSH], Ion channels, Acid Sensing Ion Channels/metabolism [MeSH], Extracellular acidity, Tumour microenvironment, Cerebellar Neoplasms, Large-Conductance Calcium-Activated Potassium Channel alpha Subunits, Cell Size
Description: Fast growing solid tumors are frequently surrounded by an acidic microenvironment. Tumor cells employ a variety of mechanisms to survive and proliferate under these harsh conditions. In that regard, acid-sensitive membrane receptors constitute a particularly interesting target, since they can affect cellular functions through ion flow and second messenger cascades. Our knowledge of these processes remains sparse, however, especially regarding medulloblastoma, the most common pediatric CNS malignancy. In this study, using RT-qPCR, whole-cell patch clamp, and Ca2+-imaging, we uncovered several ion channels and a G protein-coupled receptor, which were regulated directly or indirectly by low extracellular pH in DAOY and UW228 medulloblastoma cells. Acidification directly activated acid-sensing ion channel 1a (ASIC1a), the proton-activated Cl− channel (PAC, ASOR, or TMEM206), and the proton-activated G protein-coupled receptor OGR1. The resulting Ca2+ signal secondarily activated the large conductance calcium-activated potassium channel (BKCa). Our analyses uncover a complex relationship of these transmembrane proteins in DAOY cells that resulted in cell volume changes and induced cell death under strongly acidic conditions. Collectively, our results suggest that these ion channels in concert with OGR1 may shape the growth and evolution of medulloblastoma cells in their acidic microenvironment.
Document Type: Article
Other literature type
Language: English
ISSN: 1432-2013
0031-6768
DOI: 10.1007/s00424-024-02964-7
DOI: 10.21203/rs.3.rs-3930823/v1
DOI: 10.18154/rwth-2024-05109
Access URL: https://pubmed.ncbi.nlm.nih.gov/38627262
https://repository.publisso.de/resource/frl:6513784
https://publications.rwth-aachen.de/record/986262
Rights: CC BY
Accession Number: edsair.doi.dedup.....59327c72940dbcbe48dc54ac9111d77c
Database: OpenAIRE
Description
Abstract:Fast growing solid tumors are frequently surrounded by an acidic microenvironment. Tumor cells employ a variety of mechanisms to survive and proliferate under these harsh conditions. In that regard, acid-sensitive membrane receptors constitute a particularly interesting target, since they can affect cellular functions through ion flow and second messenger cascades. Our knowledge of these processes remains sparse, however, especially regarding medulloblastoma, the most common pediatric CNS malignancy. In this study, using RT-qPCR, whole-cell patch clamp, and Ca2+-imaging, we uncovered several ion channels and a G protein-coupled receptor, which were regulated directly or indirectly by low extracellular pH in DAOY and UW228 medulloblastoma cells. Acidification directly activated acid-sensing ion channel 1a (ASIC1a), the proton-activated Cl− channel (PAC, ASOR, or TMEM206), and the proton-activated G protein-coupled receptor OGR1. The resulting Ca2+ signal secondarily activated the large conductance calcium-activated potassium channel (BKCa). Our analyses uncover a complex relationship of these transmembrane proteins in DAOY cells that resulted in cell volume changes and induced cell death under strongly acidic conditions. Collectively, our results suggest that these ion channels in concert with OGR1 may shape the growth and evolution of medulloblastoma cells in their acidic microenvironment.
ISSN:14322013
00316768
DOI:10.1007/s00424-024-02964-7