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

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 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

Language: Английский

Evolutionary study and structural basis of proton sensing by Mus GPR4 and Xenopus GPR4 DOI
Xin Wen,

Pan Shang,

Haidi Chen

et al.

Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

4
Cryo-EM structure of an activated GPR4–Gs signaling complex DOI Creative Commons
Yitong Ma, Yijie Wang,

Mengyuan Tang

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 11, 2025

G protein-coupled receptor 4 (GPR4) belongs to the subfamily of proton-sensing GPCRs (psGPCRs), which detect pH changes in extracellular environment and regulate diverse physiological responses. GPR4 was found be overactivated acidic tumor microenvironment as well inflammation sites, with a triad residues within transmembrane domain identified crucial for proton sensing. However, 3D structure remains unknown, roles other conserved psGPCRs are not understood. Here we report cryo-electron microscopy (cryo-EM) structures active zebrafish at both 6.5 8.5, each highlighting distribution histidine region. Cell-based assays show that these ionizable moderately influence capacity GPR4, compared more significant effects residues. Furthermore, reveal cluster aromatic orthosteric pocket may propagate signaling intercellular region via repacking patch central This study provides framework future functional investigation psGPCRs. The low Here, authors cryo-EM provide insight into structural features sensing mechanism.

Language: Английский

Citations

2
Kidney metabolism and acid–base control: back to the basics DOI Creative Commons
Pedro Henrique Imenez Silva, Nilufar Mohebbi

Pflügers Archiv - European Journal of Physiology, Journal Year: 2022, Volume and Issue: 474(8), P. 919 - 934

Published: May 5, 2022

Kidneys are central in the regulation of multiple physiological functions, such as removal metabolic wastes and toxins, maintenance electrolyte fluid balance, control pH homeostasis. In addition, kidneys participate systemic gluconeogenesis production or activation hormones. Acid-base conditions influence all these functions concomitantly. Healthy properly coordinate a series responses face acute chronic acid-base disorders. However, injured have reduced capacity to adapt challenges. Chronic kidney disease patients an example individuals typically exposed progressive acidosis. Their organisms undergo alterations that brake large detrimental changes homeostasis several parameters, but may also operate further drivers damage. disorders lead not only mechanisms involved balance maintenance, they affect other tightly wired it. this review article, we explore basic renal activities show how interconnected cell energy metabolism important intracellular activities. These intertwined relationships been investigated for more than century, modern conceptual organization events is lacking. We propose indissociably interacts with pathways drive progression disease, inflammation metabolism, independent etiology.

Language: Английский

Citations

55
The pathophysiology of distal renal tubular acidosis DOI
Carsten A. Wagner, Robert J. Unwin, Sergio Camilo Lopez-Garcia

et al.

Nature Reviews Nephrology, Journal Year: 2023, Volume and Issue: 19(6), P. 384 - 400

Published: April 4, 2023

Language: Английский

Citations

38
A Narrative Review of Cytokine Networks: Pathophysiological and Therapeutic Implications for Inflammatory Bowel Disease Pathogenesis DOI Creative Commons

Marek Vébr,

Renata Pomahačová, Josef Sýkora

et al.

Biomedicines, Journal Year: 2023, Volume and Issue: 11(12), P. 3229 - 3229

Published: Dec. 6, 2023

Inflammatory bowel disease (IBD) is a lifelong inflammatory immune mediated disorder, encompassing Crohn's (CD) and ulcerative colitis (UC); however, the cause specific pathogenesis of IBD yet incompletely understood. Multiple cytokines produced by different cell types results in complex functional networks that constitute highly regulated messaging network signaling pathways. Applying biological mechanisms underlying at single omic level, technologies genetic engineering enable quantification pattern released new insights into cytokine landscape IBD. We focus on existing literature dealing with biology pro- or anti-inflammatory interactions facilitate cell-based modulation system for inflammation. summarize main roles substantial related to homeostatic tissue functions remodeling IBD, which may be specifically valuable successful cytokine-targeted therapies via marketed products. Cytokines their receptors are validated targets multiple therapeutic areas, we review current strategies intervention developing therapies. New biologics have shown efficacy last few decades management IBD; unfortunately, many patients nonresponsive develop therapy resistance over time, creating need novel therapeutics. Thus, treatment options beyond immune-modifying anti-TNF agents combination expanding rapidly. Further studies needed fully understand response, cytokines, direct pathogenetic relevance regarding individually tailored, safe efficient targeted-biotherapeutics.

Language: Английский

Citations

25
Role of proton-activated G protein-coupled receptors in pathophysiology DOI
Pedro Henrique Imenez Silva, Niels Olsen Saraiva Câmara, Carsten A. Wagner

et al.

AJP Cell Physiology, Journal Year: 2022, Volume and Issue: 323(2), P. C400 - C414

Published: June 27, 2022

Local acidification is a common feature of many disease processes such as inflammation, infarction, or solid tumor growth. Acidic pH not merely sequela but contributes to recruitment and regulation immune cells, modifies metabolism parenchymal, modulates fibrosis, vascular permeability, oxygen availability, consumption, invasiveness impacts on cell survival. Thus, multiple pH-sensing mechanisms must exist in cells involved these processes. These sensors play important roles normal physiology pathophysiology, hence might be attractive targets for pharmacological interventions. Among the mechanisms, OGR1 ( GPR68), GPR4 GPR4), TDAG8 GPR65) have emerged molecules. G protein-coupled receptors are widely expressed, upregulated inflammation tumors, sense changes extracellular range between 8 6, modulating key biology, fibrosis. This review discusses features highlights states pathways affected by their activity.

Language: Английский

Citations

30
Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy DOI Creative Commons
Qian Cheng, Xiao‐Lei Shi, Qilin Li

et al.

Advanced Science, Journal Year: 2023, Volume and Issue: 11(3)

Published: Nov. 8, 2023

Abstract Increasing numbers of studies have shown that tumor cells prefer fermentative glycolysis over oxidative phosphorylation to provide a vast amount energy for fast proliferation even under oxygen‐sufficient conditions. This metabolic alteration not only favors cell progression and metastasis but also increases lactate accumulation in solid tumors. In addition serving as byproduct glycolytic cells, plays central role the construction acidic immunosuppressive microenvironment, resulting therapeutic tolerance. Recently, targeted drug delivery inherent properties nanomaterials attracted great attention, research on modulating metabolism based enhance antitumor therapy has exploded. this review, advanced strategies interfere with are discussed, including inhibiting anabolism, promoting catabolism, disrupting “lactate shuttle”. Furthermore, recent advances combining modulation other therapies, chemotherapy, immunotherapy, photothermal therapy, reactive oxygen species‐related etc., which achieved cooperatively enhanced outcomes, summarized. Finally, foreseeable challenges prospective developments reviewed future development field.

Language: Английский

Citations

23
The acid-sensing receptor GPR65 on tumor macrophages drives tumor growth in obesity DOI Open Access
Sreya Bagchi,

Robert Yuan,

Han-Li Huang

et al.

Science Immunology, Journal Year: 2024, Volume and Issue: 9(100)

Published: Oct. 18, 2024

Multiple cancers, including colorectal cancer (CRC), are more frequent and often aggressive in individuals with obesity. Here, we showed that macrophages accumulated within tumors of patients obesity CRC obese mice they promoted accelerated tumor growth. These changes were initiated by oleic acid accumulation subsequent cell–derived production driven macrophage signaling through the acid-sensing receptor GPR65. We found a similar role for GPR65 hepatocellular carcinoma (HCC) mice. Tumors or HCC also exhibited increased expression, suggesting mechanism revealed here may contribute to growth range obesity-associated cancers represent potential therapeutic target.

Language: Английский

Citations

8
Cerebrospinal fluid pH regulation DOI
Helle Hasager Damkier, Jeppe Prætorius

Pflügers Archiv - European Journal of Physiology, Journal Year: 2024, Volume and Issue: 476(4), P. 467 - 478

Published: Feb. 22, 2024

Language: Английский

Citations

4
Acid‐sensing receptor GPR4 plays a crucial role in lymphatic cancer metastasis DOI Creative Commons
Masako Nakanishi,

Akiya Ibe,

Kiyoto Morishita

et al.

Cancer Science, Journal Year: 2024, Volume and Issue: 115(5), P. 1551 - 1563

Published: Feb. 27, 2024

Cancer tissues exhibit an acidic microenvironment owing to the accumulation of protons and lactic acid produced by cancer inflammatory cells. To examine role in lymphatic metastasis, gene expression profiling was conducted using human dermal endothelial cells (HDLECs) treated with a low pH medium. Microarray set enrichment analysis revealed that treatment induced inflammation-related genes HDLECs, including encoding chemokines adhesion molecules. Acid treatment-induced C-X3-C motif chemokine ligand 1 (CX3CL1) C-X-C 6 (CXCL6) autocrinally promoted growth tube formation HDLECs. The vascular cell molecule (VCAM-1) increased HDLECs after time-dependent manner, which, turn, enhanced their melanoma Among various acid-sensing receptors, basally expressed G protein-coupled receptor 4 (GPR4), which augmented under microenvironment. induction or VCAM-1 conditions attenuated GPR4 knockdown In addition, lymph node metastases mouse model were suppressed administering anti-VCAM-1 antibody antagonist. These results suggest modifies function via GPR4, thereby promoting metastasis. Acid-sensing receptors downstream molecules might serve as preventive therapeutic targets cancer.

Language: Английский

Citations

4