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 DOI Creative Commons

Karolos‐Philippos Pissas,

Stefan Gründer,

Yuemin Tian

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Фев. 9, 2024

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 particularly interesting target, since they can affect cellular functions through ion flow second messenger cascades. Our knowledge processes remains sparse, however, especially regarding medulloblastoma, the most common pediatric CNS malignancy. this study, using RT-qPCR, whole-cell patch clamp Ca2+-imaging, we uncovered several channels G protein-coupled receptor, which were regulated directly or indirectly low extracellular pH in DAOY UW228 medulloblastoma cells. Acidification activated acid-sensing channel 1a (ASIC1a), proton-activated Cl−channel (PAC, ASOR, TMEM206), receptor OGR1. The resulting Ca2+signal secondarily large conductance calcium-activated potassium (BKCa). analyses uncover complex relationship transmembrane proteins resulted cell volume changes induced death strongly Collectively, our results suggest concert with OGR1 may shape growth evolution MB their

Язык: Английский

Inhibition of proton sensor GPR68 suppresses endothelial dysfunction and acute lung injury caused by Staphylococcus aureus bacterial particles DOI Creative Commons

Pratap Karki,

Yunbo Ke,

Chen‐Ou Zhang

и другие.

The FASEB Journal, Год журнала: 2025, Номер 39(3)

Опубликована: Фев. 5, 2025

Abstract Lung bacterial infections, including hospital‐acquired pneumonia, remain a serious problem for public health. Endothelial cell (EC) exposure to heat‐killed Staphylococcus aureus (HKSA) represents clinical scenario of high titers killed particles present in the host after antibiotic therapy, which triggers inflammatory cascades, cytokine storms, and EC dysfunction leading acute lung injury (ALI). GPR68 is member proton‐sensing G protein‐coupled receptor family. Acting as pH sensor, becomes activated upon reduction contributes pathologic responses by activating ER stress unfolded protein response. This study investigated role HKSA‐induced ALI. HKSA robustly increased mRNA levels human pulmonary directly stimulated activity. A selective small molecule inhibitor, OGM‐8345, attenuated permeability protected junction integrity. OGM‐8345 inhibited activation genes TNF‐α, IL‐6, IL‐8, IL‐1β, CXCL5 decreased secretion HKSA‐challenged EC. Co‐treatment with activator Ogerin or medium acidification 6.5 augmented dysfunction, was rescued OGM‐8345. Intratracheal injection vascular leak inflammation mice were monitored Evans blue extravasation, count bronchoalveolar lavage, expression genes. ALI barrier We show first time mediating strong potential therapeutic treatment pathogen‐induced associated tissue acidification.

Язык: Английский

Процитировано

0
Loss of proton‐sensing GPR4 reduces tumor progression in mouse models of colon cancer DOI Creative Commons
Leonie Perren,

Moana Busch,

Pedro A. Ruiz

и другие.

Molecular Oncology, Год журнала: 2025, Номер unknown

Опубликована: Май 21, 2025

Язык: Английский

Процитировано

0
Purinergic ligands induce extracellular acidification and increased ATP turnover in HepG2 cells DOI

Haotong Chen,

Yong Chol Han,

Abby Hearne

и другие.

Toxicology in Vitro, Год журнала: 2024, Номер 96, С. 105788 - 105788

Опубликована: Фев. 4, 2024

Язык: Английский

Процитировано

3
Protons taken hostage: Dynamic H-bond networks of the pH-sensing GPR68 DOI Creative Commons
B.M. Kapur, Filippo Baldessari,

Michalis Lazaratos

и другие.

Computational and Structural Biotechnology Journal, Год журнала: 2023, Номер 21, С. 4370 - 4384

Опубликована: Янв. 1, 2023

Proton-sensing G Protein Coupled Receptors (GPCRs) sense changes in the extracellular pH to effect cell signaling for cellular homeostasis. They tend be overexpressed solid tumors associated with acidic pH, and are of direct interest as drug targets. How proton-sensing GPCRs acidification activate upon protonation change is important understand, because it may guide design therapeutics. Lack publicly available experimental structures make challenging discriminate between conflicting mechanisms proposed proton-binding, main roles have been assigned either an histidine cluster or internal carboxylic triad. Here we present a protocol derive evaluate structural models GPR68. This approach integrates state-of-the-art homology modeling microsecond-timescale atomistic simulations, detailed assessment compatibility known features class A GPCRs. To decipher elements potential protonation-coupled conformational GPR68, used best-compatible model starting point independent simulations GPR68 different states, graph computations characterize response protonation. We found that hosts extended hydrogen-bond network inter-connects triad, which can even reach groups at cytoplasmic G-protein binding site. Taken together, results suggest relies on dynamic, networks inter-connect proton-binding sites, elicit

Язык: Английский

Процитировано

6
Recent advances in acid sensing by G protein coupled receptors DOI Creative Commons
Maike D. Glitsch

Pflügers Archiv - European Journal of Physiology, Год журнала: 2024, Номер 476(4), С. 445 - 455

Опубликована: Фев. 10, 2024

Abstract Changes in extracellular proton concentrations occur a variety of tissues over range timescales under physiological conditions and also accompany virtually all pathologies, notably cancers, stroke, inflammation trauma. Proton-activated, G protein coupled receptors are already partially active at their activity increases with rising concentrations. Their ability to monitor report changes hence pH appears be involved processes, it is likely mirror some cases promote disease progression. Unsurprisingly, therefore, these pH-sensing (pHR) receive increasing attention from researchers working an expanding research areas, cellular neurophysiology systemic inflammatory processes. This review looking progress made the field pHRs past few years highlights outstanding issues.

Язык: Английский

Процитировано

2
Ca2+ Signaling in Cardiovascular Fibroblasts DOI Creative Commons
Andreas Rinne, Florentina Pluteanu

Biomolecules, Год журнала: 2024, Номер 14(11), С. 1365 - 1365

Опубликована: Окт. 27, 2024

Fibrogenesis is a physiological process required for wound healing and tissue repair. It induced by activation of quiescent fibroblasts, which first proliferate then change their phenotype into migratory, contractile myofibroblasts. Myofibroblasts secrete extracellular matrix proteins, such as collagen, to form scar. Once the terminated, most myofibroblasts undergo apoptosis. However, in some tissues, heart, remain active sensitive neurohumoral factors inflammatory mediators, lead eventually excessive organ fibrosis. Many cellular processes involved fibroblast activation, including cell proliferation, protein secretion contraction, are highly regulated intracellular Ca

Язык: Английский

Процитировано

2
OGR1 (GPR68) and TDAG8 (GPR65) Have Antagonistic Effects in Models of Colonic Inflammation DOI Open Access
Leonie Perren,

Moana Busch,

Cordelia Schuler

и другие.

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(19), С. 14855 - 14855

Опубликована: Окт. 3, 2023

G-protein-coupled receptors (GPRs), including pro-inflammatory ovarian cancer GPR1 (OGR1/GPR68) and anti-inflammatory T cell death-associated gene 8 (TDAG8/GPR65), are involved in pH sensing linked to inflammatory bowel disease (IBD). OGR1 TDAG8 show opposite effects. To determine which effect is predominant or physiologically more relevant, we deleted both models of intestinal inflammation. Combined Ogr1 Tdag8 deficiency was assessed spontaneous acute murine colitis models. Disease severity using clinical scores. Colon samples were analyzed quantitative polymerase chain reaction (qPCR) flow cytometry (FACS). In colitis, Ogr1-deficient mice showed significantly decreased scores compared with wildtype (WT) mice, while Tdag8-deficient double knockout (KO) presented similar WT. Il-10-spontaneous decreased, had increased the Il10-/- × Ogr1-/- Tdag8-/- triple KO inflammation Tdag8-/-. Absence reduced cytokines mice. IFNγ+ T-lymphocytes IL-23 T-helper cells colon The absence alleviates damage mediated by lack functional TDAG8. Both represent potential new targets for therapeutic intervention.

Язык: Английский

Процитировано

5
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 DOI Creative Commons

Karolos‐Philippos Pissas,

Stefan Gründer,

Yuemin Tian

и другие.

Pflügers Archiv - European Journal of Physiology, Год журнала: 2024, Номер 476(6), С. 923 - 937

Опубликована: Апрель 16, 2024

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 particularly interesting target, since they can affect cellular functions through ion flow second messenger cascades. Our knowledge processes remains sparse, however, especially regarding medulloblastoma, the most common pediatric CNS malignancy. this study, using RT-qPCR, whole-cell patch clamp, Ca

Язык: Английский

Процитировано

1
Proton Mechanisms of Neurotransmission and Calcium Signalling for Impulse Initiation, Development and Propagation DOI Creative Commons
Giuliano Molinari

Опубликована: Май 29, 2024

Protons are gaining increasing attention as neurotransmitters due to their extraordinary abilities rapidly transfer electrical charge, mobilize cellular calcium and modulate ion channels. How all this is possible currently the subject of in-depth studies discussions concerning not only neurophysiology, but also biological materials for artificial intelligence. This review describes some biochemical mechanisms by which protons, in combination with calcium, can initiate firing sensory neurons transmit impulses across synapses, thus supporting action Na+ K+ ions shown Hodgkin Huxley. Furthermore, put forward how many hydrolases neurotransmitters, particularly glutamate, gamma-aminobutyric acid, adenosine triphosphate acetylcholine, able generate protons. The results numerous experimental works taken into consideration indicate that protons play a fundamental role both generation transmission nerve impulse.

Язык: Английский

Процитировано

1
Proton Mechanisms of Neurotransmission and Calcium Signalling for Impulse Initiation, Development and Propagation DOI Creative Commons
Giuliano Molinari

Опубликована: Июль 31, 2024

Protons are gaining increasing attention as neurotransmitters due to their extraordinary abilities rapidly transfer electrical charge, mobilize cellular calcium and modulate ion channels. How all this is possible currently the subject of in-depth studies discussions concerning not only neurophysiology, but also biological materials for artificial intelligence. This review describes some biochemical mechanisms by which protons, in combination with calcium, can initiate firing sensory neurons transmit impulses across synapses, thus supporting action Na+ K+ ions shown Hodgkin Huxley. Furthermore, put forward how many hydrolases neurotransmitters, particularly glutamate, gamma-aminobutyric acid, adenosine triphosphate acetylcholine, able generate protons. The results numerous experimental works taken into consideration indicate that protons play a fundamental role both generation transmission nerve impulse.

Язык: Английский

Процитировано

1