Cryo-EM structure of the bicarbonate receptor GPR30 DOI Open Access
Shota Kaneda,

Airi Jo-Watanabe,

Hiroaki Akasaka

et al.

Published: July 26, 2024

G-protein-coupled receptor 30 (GPR30) is a bicarbonate that plays vital role in cellular responses to extracellular pH and ion homeostasis. Despite its significance, the mechanisms by which GPR30 interacts with ions remain elusive. There no consensus on drug targets GPR30, difficulty pharmacological analysis has limited biological discovery researches GPR30. Here, we present cryo-electron microscopy structure of human presence at 3.2 Å resolution. Our reveals unique pockets critical residues for binding activation. Functional assays demonstrate mutations these impair bicarbonate-induced activation, underscoring their importance function. This study also provides insights into G-protein coupling, highlighting structural divergence between other GPCRs. findings not only advance understanding homeostasis but pave way development high-affinity drugs targeting therapeutic interventions diseases associated acid-base imbalance.

Language: Английский

How protons pave the way to aggressive cancers DOI
Pawel Swietach, Ebbe Boedtkjer, Stine F. Pedersen

et al.

Nature reviews. Cancer, Journal Year: 2023, Volume and Issue: 23(12), P. 825 - 841

Published: Oct. 26, 2023

Language: Английский

Citations

44
Structural basis and biased signaling of proton sensation by GPCRs mediated by extracellular histidine rearrangement DOI
Lulu Guo, Kongkai Zhu, Ya-Ni Zhong

et al.

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

Published: April 1, 2025

Language: Английский

Citations

2
Bicarbonate signalling via G protein-coupled receptor regulates ischaemia-reperfusion injury DOI Creative Commons
Airi Jo‐Watanabe, Toshiki Inaba, Takahiro Osada

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 27, 2024

Homoeostatic regulation of the acid-base balance is essential for cellular functional integrity. However, little known about molecular mechanism through which regulates responses. Here, we report that bicarbonate ions activate a G protein-coupled receptor (GPCR), i.e., GPR30, leads to

Language: Английский

Citations

13
Proton perception and activation of a proton-sensing GPCR DOI

Li-Nan Chen,

Hui Zhou, Kun Xi

et al.

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

Published: April 1, 2025

Language: Английский

Citations

1
Acid-sensing ion channels and downstream signalling in cancer cells: is there a mechanistic link? DOI Creative Commons
Stefan Gründer,

Jakob Vanek,

Karolos‐Philippos Pissas

et al.

Pflügers Archiv - European Journal of Physiology, Journal Year: 2024, Volume and Issue: 476(4), P. 659 - 672

Published: Jan. 4, 2024

Abstract It is increasingly appreciated that the acidic microenvironment of a tumour contributes to its evolution and clinical outcomes. However, our understanding mechanisms by which cells detect acidosis signalling cascades it induces still limited. Acid-sensing ion channels (ASICs) are sensitive receptors for protons; therefore, they also candidates proton sensors in cells. Although non-transformed tissue, their expression mainly restricted neurons, an increasing number studies have reported ectopic ASICs not only brain cancer but different carcinomas, such as breast pancreatic cancer. because best known desensitizing ionotropic mediate rapid transient signalling, how trigger intracellular well understood. In this review, we introduce tumours functional properties ASICs, point out some conceptual problems, summarize roles cancers, highlight open questions on action Finally, propose guidelines keep ASIC research solid ground.

Language: Английский

Citations

6
Intestinal epithelial pH-sensing receptor GPR65 maintains mucosal homeostasis via regulating antimicrobial defense and restrains gut inflammation in inflammatory bowel disease DOI Creative Commons
Gengfeng Li, Jian Lin, Xiang Gao

et al.

Gut Microbes, Journal Year: 2023, Volume and Issue: 15(2)

Published: Sept. 25, 2023

Intestinal epithelial cell (IEC) regulation of barrier function and mucosal homeostasis enables the establishment a harmonious gut microenvironment. However, host-derived regulatory networks that modulate intestinal antimicrobial defenses have not been fully defined. Herein we generated mice with IEC-specific deletion Gpr65 (Gpr65ΔIEC) investigated role GPR65 using DSS- C. rodentium-induced murine colitis models. RNA sequencing analysis was conducted on colonic IECs from Gpr65fl/fl Gpr65ΔIEC mice, colonoids lines were used to evaluate pH-sensing effect GPR65. The expression determined in patients inflammatory bowel disease (IBD) DSS by qRT-PCR, Western blot, immunohistochemistry, respectively. We observed absence abrogated homeostatic programs, including production peptides (AMPs) defense response-associated proteins. displayed dysbiosis microbiota prone colitis, as characterized significantly disrupted responses, pathogen invasion, increased infiltrates inflamed colon. revealed provoked dramatic transcriptome changes respect downregulation immune responses bacteria. Forced AMP induction assays vivo or ex IEC-intrinsic signaling drove defense. Mechanistically, promoted STAT3 phosphorylation optimize responses. Epithelial line colonoid further confirmed sensing pH synergized IL-22 facilitate Finally, markedly decreased epithelia IBD mice. Our findings define an important regulating inflammation point toward potential therapeutic approach targeting treatment IBD.

Language: Английский

Citations

12
NADH-bound AIF activates the mitochondrial CHCHD4/MIA40 chaperone by a substrate-mimicry mechanism DOI Creative Commons
Chris A. Brosey, Runze Shen, John A. Tainer

et al.

The EMBO Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Abstract Mitochondrial metabolism requires the chaperoned import of disulfide-stabilized proteins via CHCHD4/MIA40 and its enigmatic interaction with oxidoreductase Apoptosis-inducing factor (AIF). By crystallizing human CHCHD4’s AIF-interaction domain an activated AIF dimer, we uncover how NADH allosterically configures to anchor β-hairpin histidine-helix motifs inner mitochondrial membrane. The structure further reveals a similarity between recognition sequences CHCHD4 substrates. NMR X-ray scattering (SAXS) solution measurements, mutational analyses, biochemistry show that substrate-mimicking shields redox-sensitive active site. Disrupting this shield critically activates substrate affinity chaperone activity. Regulatory-domain sequestration by NADH-activated directly stimulates binding folding, revealing mediates import. These results establish as integral component metazoan disulfide relay point dimeric organizational center for Importantly, regulation links AIF’s cellular NAD(H) sensing function, suggesting mechanism balance tissue-specific oxidative phosphorylation (OXPHOS) capacity availability.

Language: Английский

Citations

0
Integrated bioinformatics analysis to develop diagnostic models for malignant transformation of chronic proliferative diseases DOI Creative Commons
Hua Liu,

Sheng Lin,

Peng Chen

et al.

Blood Science, Journal Year: 2025, Volume and Issue: 7(2), P. e00226 - e00226

Published: April 7, 2025

The combined analysis of dual diseases can provide new insights into pathogenic mechanisms, identify novel biomarkers, and develop targeted therapeutic strategies. Polycythemia vera (PV) is a chronic myeloproliferative neoplasm associated with risk acute myeloid leukemia (AML) transformation. However, the nature disease transformation complicates longitudinal high-throughput sequencing studies patients PV before after AML This study aimed to diagnostic model for malignant proliferative diseases, addressing challenges early detection intervention. Integrated public datasets were analyzed differentially expressed genes (DEGs) construct weighted correlation network. Machine-learning algorithms screen potential leading development models. Clinical specimens collected validate gene expression. cMAP molecular docking predicted drugs. In vitro experiments performed assess drug efficacy in cells. CIBERSORT single-cell RNA-sequencing (scRNA-seq) analyses used explore impact hub on tumor microenvironment. We identified 24 shared between AML, which enriched immune-related pathways. Lactoferrin (LTF) G protein-coupled receptor 65 (GPR65) integrated nomogram robust predictive power. vemurafenib inhibited proliferation increased apoptosis TME has linked these biomarkers macrophages. samples confirm LTF GPR65 expression levels. developed that offers avenue diagnosis clinical management AML-related PV.

Language: Английский

Citations

0
Unraveling the proton-sensing mechanisms of G protein-coupled receptors: Insights from cryogenic electron microscopy studies DOI
Chenyang Xue, Zhongmin Liu

Molecular Cell, Journal Year: 2025, Volume and Issue: 85(8), P. 1479 - 1481

Published: April 1, 2025

Language: Английский

Citations

0
Spatially resolved analysis of microenvironmental gradient impact on cancer cell phenotypes DOI Creative Commons
Jamie Auxillos, Roxane Crouigneau, Yanfang Li

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(18)

Published: May 3, 2024

Despite the physiological and pathophysiological significance of microenvironmental gradients, e.g., for diseases such as cancer, tools generating gradients analyzing their impact are lacking. Here, we present an integrated microfluidic-based workflow that mimics extracellular pH characteristic solid tumors while enabling high-resolution live imaging of, cell motility chemotaxis, preserving capacity to capture spatial transcriptome. Our microfluidic device generates a gradient can be rapidly controlled mimic spatiotemporal changes over cancer cells embedded in 3D matrix. The reopened allowing immunofluorescence analysis selected phenotypes, well transfer matrix Visium slide spatially resolved transcriptional across gradient. This is easily adaptable other multiple types therefore prove invaluable roles biology.

Language: Английский

Citations

3