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

The Roles of Proton-Sensing G-Protein-Coupled Receptors in Inflammation and Cancer DOI Open Access

Calvin R. Justus,

Mona A. Marie, Edward J. Sanderlin

et al.

Genes, Journal Year: 2024, Volume and Issue: 15(9), P. 1151 - 1151

Published: Sept. 1, 2024

The precise regulation of pH homeostasis is crucial for normal physiology. However, in tissue microenvironments, it can be impacted by pathological conditions such as inflammation and cancer. Due to the overproduction accumulation acids (protons), extracellular characteristically more acidic inflamed tissues tumors comparison tissues. A family proton-sensing G-protein-coupled receptors (GPCRs) has been identified molecular sensors cells responding microenvironments. Herein, we review current research progress pertaining these GPCRs, including GPR4, GPR65 (TDAG8), GPR68 (OGR1), Growing evidence suggests that GPR4 are mainly pro-inflammatory, whereas primarily anti-inflammatory, various inflammatory disorders. Both anti- pro-tumorigenic effects have reported this receptors. Moreover, antagonists agonists targeting GPCRs developed evaluated preclinical models. Further warranted better understand roles pathophysiology required order exploit them potential therapeutic targets disease treatment.

Language: Английский

Citations

3
Location-biased activation of the proton-sensor GPR65 is uncoupled from receptor trafficking DOI Creative Commons
Loyda M. Morales Rodríguez, Stephanie E. Crilly, Jacob B. Rowe

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(39)

Published: Sept. 18, 2023

The canonical view of G protein–coupled receptor (GPCR) function is that trafficking tightly coupled to signaling. GPCRs remain on the plasma membrane (PM) at cell surface until they are activated, after which desensitized and internalized into endosomal compartments. This presents an interesting context for proton-sensing because more likely be activated in acidic compartments than PM. Here, we show prototypical proton-sensor GPR65 fully uncoupled from signaling, unlike other known mammalian GPCRs. internalizes localizes early late endosomes, where signal steady state, irrespective extracellular pH. Acidic environments stimulate signaling PM a dose-dependent manner, although still required full response. Receptor mutants were incapable activating cAMP trafficked normally, internalize localize Our results constitutively active suggest model changes pH reprograms spatial pattern biases location surface.

Language: Английский

Citations

8
Role of pH-sensing receptors in colitis DOI Creative Commons
Martin Hausmann, Klaus Seuwen, Cheryl de Vallière

et al.

Pflügers Archiv - European Journal of Physiology, Journal Year: 2024, Volume and Issue: 476(4), P. 611 - 622

Published: March 22, 2024

Abstract Low pH in the gut is associated with severe inflammation, fibrosis, and colorectal cancer (CRC) a hallmark of active inflammatory bowel disease (IBD). Subsequently, pH-sensing mechanisms are interest for understanding IBD pathophysiology. Tissue hypoxia acidosis—two contributing factors to pathophysiology—are linked IBD, their interplay highly relevant development new therapeutic options. One member proton-sensing G protein-coupled receptor (GPCR) family, GPR65 (T-cell death-associated gene 8, TDAG8), was identified as susceptibility large genome-wide association study. In response acidic extracellular pH, induces an anti-inflammatory response, whereas two other receptors, GPR4 GPR68 (ovarian 1, OGR1), mediate pro-inflammatory responses. Here, we review current knowledge on role these receptors IBD-associated fibrosis cancer, well colitis-associated (CAC). We also describe emerging small molecule modulators opportunities treatment IBD.

Language: Английский

Citations

2
Recent advances in acid sensing by G protein coupled receptors DOI Creative Commons
Maike D. Glitsch

Pflügers Archiv - European Journal of Physiology, Journal Year: 2024, Volume and Issue: 476(4), P. 445 - 455

Published: Feb. 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.

Language: Английский

Citations

2
GPR65 as a potential novel therapeutic target for the treatment of hepatic fibrosis DOI Creative Commons
Leila Gobejishvili

Military Medical Research, Journal Year: 2024, Volume and Issue: 11(1)

Published: Jan. 8, 2024

Language: Английский

Citations

1
ASIC3-activated key enzymes of de novo lipid synthesis supports lactate-driven EMT and the metastasis of colorectal cancer cells DOI Creative Commons

Xing Wan,

Feng Li, Zhigui Li

et al.

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Aug. 2, 2024

Acidic microenvironments is a cancer progression driver, unclear core mechanism hinders the discovery of new diagnostic or therapeutic targets. ASIC3 an extracellular proton sensor and acid-sensitive, but its role in acidic tumor microenvironment colorectal not reported. Functional analysis data show that cells respond to specific concentration lactate accelerate invasion metastasis, main actor this process. Mechanism reveal de novo lipid synthesis regulatory process ASIC3, down-regulated increases interacts with ACC1 SCD1, which are key enzymes pathway, interaction results increased unsaturated fatty acids, turn induce EMT promote overexpression reduces TME-enhanced metastasis. Clinical samples also exhibit decreased expression, low expression associated metastasis stage cancer. This study first identify ASIC3-ACC1/SCD1 axis acid-enhanced The pattern differs significantly from other types cancers, may serve as novel reliable marker for microenvironmental cancer, potentially target.

Language: Английский

Citations

1
Doxorubicin-Induced Platelet Activation and Clearance Relieved by Salvianolic Acid Compound: Novel Mechanism and Potential Therapy for Chemotherapy-Associated Thrombosis and Thrombocytopenia DOI Creative Commons
Wenjing Ma,

Zackary Rousseau,

Sladjana Slavkovic

et al.

Pharmaceuticals, Journal Year: 2022, Volume and Issue: 15(12), P. 1444 - 1444

Published: Nov. 22, 2022

Doxorubicin (Dox) is a widely utilized chemotherapeutic; however, it carries side effects, including drug-induced immune thrombocytopenia (DITP) and increased risk of venous thromboembolism (VTE). Currently, the mechanisms for Dox-associated DITP VTE are poorly understood, an effective inhibitor to relieve these complications remains be developed. In this study, we found that Dox significantly induced platelet activation enhanced phagocytosis by macrophages accelerated clearance. Importantly, determined salvianolic acid C (SAC), water-soluble compound derived from Danshen root traditionally used treat cardiovascular diseases, inhibited Dox-induced more effectively than current standard-of-care anti-platelet drugs aspirin ticagrelor. Mechanism studies with tyrosine kinase inhibitors indicate contributions phospholipase C, spleen kinase, protein signaling pathways in activation. We further demonstrated platelet-cancer cell interaction, which was ameliorated SAC. Taken together, findings suggest SAC may promising therapy reduce DITP, VTE, repercussions amplified interaction tumor microenvironment.

Language: Английский

Citations

6
Ovarian cancer G protein-coupled receptor 1 deficiency exacerbates crystal deposition and kidney injury in oxalate nephropathy in female mice DOI Creative Commons
Nima Yassini,

Janine Sprenger,

Eva Maria Pastor Arroyo

et al.

Clinical Science, Journal Year: 2023, Volume and Issue: 137(14), P. 1013 - 1025

Published: July 1, 2023

Abstract Ovarian cancer G protein-coupled receptor 1 (OGR1) (Gpr68) and 4 (GPR4) (Gpr4) are proton-activated receptors that stimulated upon increased extracellular acidity. These have various physiological pathophysiological roles in renal acid–base physiology, tissue inflammation, fibrosis among others. Their function injured tissue, however, remains mostly unclear. To address this, we investigated their role crystalline nephropathy by increasing the oxalate intake of GPR4 KO OGR1 mice. After 10 days high-oxalate recovery, crystal content, histopathology, filtration function, inflammation were assessed. While deficiency did not show major alterations disease progression, mice had higher urinary calcium levels exacerbated accumulation accompanied decreased creatinine clearance urea excretion a presence regulatory T (Treg) cells kidney tissue. When lowering severity injury, more prone to develop nephropathy. In this setting, displayed an activation immune system production proinflammatory cytokines macrophages. Taken together, acute setting oxalate-induced nephropathy, lack (GPCR) does influence disease. deficiency, increases deposition leading impaired function. Thus, may be important limit deposition, which might subsequently relevant for pathophysiology stones or other crystallopathies.

Language: Английский

Citations

3
American Journal of Physiology-Cell Physiology in 2022: at a glance DOI
Eric Delpire, Thomas J. Hawke, Karthikeyan Mythreye

et al.

AJP Cell Physiology, Journal Year: 2023, Volume and Issue: 324(2), P. C553 - C557

Published: Jan. 16, 2023

Language: Английский

Citations

1
The mechanisms of alkali therapy in targeting renal diseases DOI
Pedro Henrique Imenez Silva,

Donald E. Wesson,

Carsten A. Wagner

et al.

Biochemical Society Transactions, Journal Year: 2023, Volume and Issue: 51(1), P. 223 - 232

Published: Feb. 6, 2023

Chronic kidney disease (CKD) is characterized by progressive reduction in function and treatments aiming at stabilizing or slowing its progression may avoid delay the necessity of replacement therapy increased mortality associated with reduced function. Metabolic acidosis, less severe stages acid stress continuum, are common consequences CKD some interventional studies support that correction slows to end-stage disease. This can be achieved mineral alkali form bicarbonate citrate salts, ingestion diets fewer acid-producing food components more base-producing components, a pharmacological approach. In this mini-review article, we summarize potential mechanisms involved beneficial effects therapy. We also discuss perspectives field challenges must overcome advance our understanding such mechanisms.

Language: Английский

Citations

1